Piperidinone derivatives as MDM2 inhibitors for the treatment of cancer

ABSTRACT

The present invention provides MDM2 inhibitor compounds of Formula I, 
     
       
         
         
             
             
         
       
         
         
           
             wherein the variables are defined above, which compounds are useful as therapeutic agents, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. provisional patent applicationNo. 61/351,827, filed 4 Jun. 2010, U.S. provisional application No.61/352,322, filed 7 Jun. 2010 and 61/452,578, filed 14 Mar. 2011, thecontents of which applications are incorporated by reference herein intheir entirety.

FIELD OF THE INVENTION

The present invention relates to compounds that are MDM2 inhibitors thatare useful as therapeutic agents, particularly for the treatment ofcancers. The invention also relates to pharmaceutical compositions thatcontain an MDM2 inhibitor.

BACKGROUND OF THE INVENTION

p53 is a tumor suppressor and transcription factor that responds tocellular stress by activating the transcription of numerous genesinvolved in cell cycle arrest, apoptosis, senescence, and DNA repair.Unlike normal cells, which have infrequent cause for p53 activation,tumor cells are under constant cellular stress from various insultsincluding hypoxia and pro-apoptotic oncogene activation. Thus, there isa strong selective advantage for inactivation of the p53 pathway intumors, and it has been proposed that eliminating p53 function may be aprerequisite for tumor survival. In support of this notion, three groupsof investigators have used mouse models to demonstrate that absence ofp53 function is a continuous requirement for the maintenance ofestablished tumors. When the investigators restored p53 function totumors with inactivated p53, the tumors regressed.

p53 is inactivated by mutation and/or loss in 50% of solid tumors and10% of liquid tumors. Other key members of the p53 pathway are alsogenetically or epigenetically altered in cancer. MDM2, an oncoprotein,inhibits p53 function, and it is activated by gene amplification atincidence rates that are reported to be as high as 10%. MDM2, in turn,is inhibited by another tumor suppressor, p14ARF. It has been suggestedthat alterations downstream of p53 may be responsible for at leastpartially inactivating the p53 pathway in p53^(WT) tumors (p53wildtype). In support of this concept, some p53^(WT) tumors appear toexhibit reduced apoptotic capacity, although their capacity to undergocell cycle arrest remains intact. One cancer treatment strategy involvesthe use of small molecules that bind MDM2 and neutralize its interactionwith p53. MDM2 inhibits p53 activity by three mechanisms: 1) acting asan E3 ubiquitin ligase to promote p53 degradation; 2) binding to andblocking the p53 transcriptional activation domain; and 3) exporting p53from the nucleus to the cytoplasm. All three of these mechanisms wouldbe blocked by neutralizing the MDM2-p53 interaction. In particular, thistherapeutic strategy could be applied to tumors that are p53^(WT), andstudies with small molecule MDM2 inhibitors have yielded promisingreductions in tumor growth both in vitro and in vivo. Further, inpatients with p53-inactivated tumors, stabilization of wildtype p53 innormal tissues by MDM2 inhibition might allow selective protection ofnormal tissues from mitotic poisons.

The present invention relates to compounds capable of inhibiting theinteraction between p53 and MDM2 and activating p53 downstream effectorgenes. As such, compounds of the present invention would be useful inthe treatment of cancers, bacterial infections, viral infections, ulcersand inflammation. In particular, the compounds of the present inventionare useful to treat solid tumors such as: breast, colon, lung andprostate tumors; and liquid tumors such as lymphomas and leukemias. Asused herein, MDM2 means a human MDM2 protein and p53 means a human p53protein. It is noted that human MDM2 can also be referred to as HDM2 orhMDM2.

SUMMARY OF THE INVENTION

The present invention relates to piperidinone derivatives of Formula I.

enantiomers, diastereomers and pharmaceutically acceptable saltsthereof,wherein

-   Q is a bond or optionally can be selected from O, NR⁷ and S(O)_(v),    when n* is an integer from 1 to 6,-   Z is C═O or S(═O)₂-   R^(a) is at each occurrence independently selected from H,    (C₁-C₃)alkyl, (halo)(C₁-C₃)alkyl, (hydroxy)(C₁-C₃)alkyl,    (alkoxy)(C₁-C₃)alkyl, or cyano;-   R^(b) is H, halo, (C₁-C₃)alkyl, (halo)(C₁-C₃)alkyl,    (hydroxy)(C₁-C₃)alkyl, (alkoxy)(C₁-C₃)alkyl, or cyano;-   R^(c) and R^(d) are independently H, halo, (C₁-C₃)alkyl,    (C₁-C₃)alkoxy, (halo)(C₁-C₃)alkyl, (halo)(C₁-C₃)alkoxy,    (alkoxy)(C₁-C₃)alkyl, (hydroxy)(C₁-C₃)alkyl;-   or R^(c) and R^(d) may optionally combine to form a spiro-cycloalkyl    or heterocyclo ring system;-   R^(e) is (a) H, or halo; or    -   (b) (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocyclo, cyano,        halogen, hydroxyl, —OR⁵, NR⁷R⁸, heterocycloalkyl, any of which        may be optionally substituted with 1 or more R^(x) groups as        allowed by valence.-   or R^(e) and any one of the R′ or R″ groups may optionally combine    to form a spiro-cycloalkyl or heterocyclo ring system;-   or R^(d) and any one of the R′ or R″ groups may optionally combine    to form a fused cycloalkyl or heterocyclo ring system;-   or R^(d) and R^(e) may optionally combine to form a fused cycloalkyl    or heterocyclo ring system;-   R′ and R″ at each occurrence, respectively, are independently H,    halo, (C₁-C₃)alkyl, (C₁-C₃)alkoxy, (halo)(C₁-C₃)alkyl,    (halo)(C₁-C₃)alkoxy, (alkoxy)(C₁-C₃)alkyl, (hydroxy)(C₁-C₃)alkyl,    —S—(C₁-C₃)alkyl, C(O)(C₁-C₃)alkyl, —NR⁷R⁸, or hydroxyl or R′ and R″    bound to the same carbon atom may optionally combine to form ═O;-   or R′ and R″ bound to the same carbon atom may optionally combine to    form a spiro-fused cycloalkyl or heterocyclo ring system-   R¹ is    -   (a) —COOH, —C(O)OR¹⁰, —C(O)NHOH, —C(O)NH—NH₂, —C(O)NHS(O)₂R¹⁰,        —S(O)₂NHC(O)R¹⁰, —S(O)₂NR⁷R⁸, —NR⁷C(O)R¹⁰, —NR⁷C(O)OR⁵,        —C(O)NR⁷R⁸, —NR⁷S(O)₂R¹⁰, or —NR⁷C(O)NR⁷R⁸, —S(O)_(v)R¹⁰, or CN;    -   (b) heteroaryl or heterocyclo either of which may be optionally        independently substituted with one or more R^(x) groups as        allowed by valence;-   R² is-   (a) —NR⁷R⁸, NR⁷C(O)OR¹⁰, NR⁷C(O)NR⁷R¹⁰, or —C(R^(a))R⁵R⁶;-   (b) aryl, heteroaryl, cycloalkyl, or heterocyclo any of which may be    optionally independently substituted with one or more R^(x) groups    as allowed by valence;-   R³ and R⁴ are independently aryl or heteroaryl, either of which may    be optionally independently substituted with one or more R^(x)    groups as allowed by valence;    -   or either R³ and R^(a) together with the ring carbon atom to        which they are both bonded,    -   or R⁴ and R^(b) together with the ring carbon atom to which they        are both bonded may optionally combine to form a spiro-fused        bicyclic ring system selected from

-   -   wherein K is —O—, —NR⁷—, or —C(═O)NR⁷—,

-   R⁵, and R⁶ at each occurrence, respectively, are independently    selected from    -   (a) H and CN; or    -   (b) -(alkylene)_(t)-OH, -(alkylene)_(t)-OR⁹,        -(alkylene)_(t)-SR⁹, -(alkylene)_(t)-NR¹⁰R¹¹,        -(alkylene)_(t)-C(O)R⁹, -(alkylene)_(t)-C(O)OR⁹,        -(alkylene)_(t)-OC(O)R⁹, -(alkylene)_(t)-S(O)_(v)R⁹,        -(alkylene)_(t)-NHS(O)₂R¹⁰, -(alkylene)_(t)-N(R¹¹)S(O)₂R¹⁰,        -(alkylene)_(t)    -   —NR¹⁰C(O)R⁹, C(O)NR¹⁰R¹¹, NR¹⁰S(O)₂R⁹, S(O)₂NR¹⁰, and        NR¹⁰C(O)NR¹⁰R¹¹; or    -   (a) haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl,        C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, (C₃₋₈-cycloalkyl)(C₁₋₃alkyl),        C₄₋₈-cycloalkenyl, aryl, aryl(C₁₋₃-alkyl) heteroaryl,        heteroaryl(C₁₋₃-alkyl), heterocyclo and heterocyclo(C₁₋₃-alkyl)        m any of which may be optionally independently substituted with        one or more R^(x) groups as allowed by valence;

-   R⁷, and R⁸ at each occurrence, respectively, are independently    selected from H, C₁₋₆-alkyl, halo(C₁₋₆)-alkyl, cycloalkyl,    C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl, heteroaryl, heterocyclo,    arylalkyl, heteroarylalkyl, heterocyclo(C₁₋₁₀alkyl), and    (C₃₋₈-cycloalkyl)(C₁₋₃alkyl), any of which may be optionally    substituted as allowed by valence with one or more R^(x); or R⁷ and    R⁸ may combine to form a C₄-C₈-heterocyclo ring optionally    substituted with one or more R^(x);

-   R⁹ is    -   haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,        C₃₋₈-cycloalkyl, (C₃₋₈-cycloalkyl)(C₁₋₃alkyl),        C₄₋₈-cycloalkenyl, aryl, heteroaryl, and heterocyclo any of        which may be optionally independently substituted with one or        more R^(x) groups as allowed by valence;

-   R¹⁰ and R¹¹ at each occurrence, respectively, are independently    selected from alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,    heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl,    heterocycloalkyl, and cycloalkylalkyl, any of which may be    optionally substituted as allowed by valence with one or more R^(x);    -   or R¹⁰ and R¹¹ may combine to form a heterocyclo ring optionally        substituted with one or more R^(x);

-   R^(x) at each occurrence is independently, deuterium, halo, cyano,    nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl, heterocycloalkyl,    -(alkylene)_(t)-OR*,    -   -(alkylene)_(t)-S(O)_(v)R*, -(alkylene)_(t)-NR⁺R⁺⁺,        -(alkylene)_(t)-C(═O)R*, -(alkylene)_(t)-C(═S)R*,        -(alkylene)_(t)-C(═O)OR*, -(alkylene)_(t)-OC(═O)R*,        -(alkylene)_(t)-C(═S)OR*, -(alkylene)_(t)-C(═O)NR⁺R⁺⁺,        -(alkylene)_(t)-C(═S)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)NR⁺R⁺⁺,        -(alkylene)_(t)-N(R⁺)C(═S)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)R*,        -(alkylene)_(t)-N(R⁺)C(═S)R*, -(alkylene)_(t)-OC(═O)NR⁺R⁺⁺,        -(alkylene)_(t)-OC(═S)NR⁺R⁺⁺, -(alkylene)_(t)-SO₂NR⁺R⁺⁺,        -(alkylene)_(t)-N(R⁺)SO₂R*, -(alkylene)_(t)-N(R⁺)SO₂NR⁺R⁺⁺,        -(alkylene)_(t)-N(R⁺)C(═O)OR*, -(alkylene)_(t)-N(R⁺)C(═S)OR*, or        -(alkylene)_(t)-N(R⁺)SO₂R*;

-   wherein said alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,    cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl,    heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groups may be    further independently substituted with one or more halo, cyano, oxo,    -(alkylene)_(t)-OR*, -(alkylene)_(t)-S(O)_(v)R*,    -(alkylene)_(t)-NR⁺R⁺⁺, -(alkylene)_(t)-C(═O)R*,    -(alkylene)_(t)-C(═S)R*, -(alkylene)_(t)-C(═O)OR*,    -(alkylene)_(t)-OC(═O)R*, -(alkylene)_(t)-C(═S)OR*,    -(alkylene)_(t)-C(═O)NR⁺R⁺⁺, -(alkylene)_(t)-C(═S)NR⁺R⁺⁺,    -(alkylene)_(t)-N(R⁺)C(═O)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═S)NR⁺R⁺⁺,    -(alkylene)_(t)-N(R⁺)C(═O)R*, -(alkylene)_(t)-N(R⁺)C(═S)R*,    -(alkylene)_(t)-OC(═O)NR⁺R⁺⁺, -(alkylene)_(t)-OC(═S)NR⁺R⁺⁺,    -(alkylene)_(t)-SO₂NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)SO₂R*,    -(alkylene)_(t)-N(R⁺)SO₂NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)OR*,    -(alkylene)_(t)-N(R⁺)C(═S)OR*, or -(alkylene)_(t)-N(R⁺)SO₂R*;

-   R* is    -   haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,        C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, aryl, heteroaryl, and        heterocyclo    -   R⁺ and R⁺⁺ are independently H, alkyl, haloalkyl, cycloalkyl,        alkenyl, alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,        heteroarylalkyl, heterocycloalkyl, and cycloalkylalkyl,

-   or R⁺ and R⁺⁺ bound to the same nitrogen atom may optionally combine    to form a heterocyclo ring system;

-   m is 1, 2 or 3

-   n and n* are each independently selected from 0 and integers from 1    to 6;

-   p is 0, 1, 2 or 3;

-   t at each occurrence is independently 0 or an integer from 1 to 6;

-   v at each occurrence is independently 0, 1 or 2;

Preferred compounds within the scope of Formula I include compoundswherein R² is —C(H)R⁵R⁶ or —NR⁷R⁸, phenyl or pyridine, the phenyl or thepyridyl may be optionally substituted with one or more R^(x) as allowedby valence.

Preferred compounds within the scope of Formula I include compoundswherein R² is R² is selected from

-   -   and any of which may be optionally substituted with one or more        R^(x) groups as allowed by valence.

Preferred compounds within the scope of Formula I include compoundswherein R¹ is

or a heterocycle selected from

(most preferentially

or a heterocycle selected from

Preferred compounds within the scope of Formula I include compounds ofFormula IA:

enantiomers, diastereomers and pharmaceutically acceptable salts thereofwherein q and p are each independently 0, 1, 2 or 3. Preferred compoundsof Formula IA include compounds containing preferred R¹ and R² groupspreviously mentioned.

Preferred compounds within the scope of Formula I include compounds ofFormula IB:

enantiomers, diastereomers and pharmaceutically acceptable salts thereofwherein q and p are each independently 0, 1, 2 or 3. Preferred compoundsof Formula IB include compounds containing preferred R¹ and R² groupspreviously mentioned Preferred compounds within the scope of formula Iinclude compounds of Formula IC:

enantiomers, diastereomers and pharmaceutically acceptable salts thereofwherein q and p are each independently 0, 1, 2 or 3. Preferred compoundsof Formula IC include compounds containing preferred R¹ and R² groupsmentioned herein.

Preferred compounds within the scope of Formulae IA, IB and IC furtherinclude compounds wherein R² is selected from

-   -   and any of which may be optionally substituted with one or more        R^(x) groups as allowed by valence.

In another aspect, aspect A, the present invention provides compounds ofFormula I:

or a pharmaceutically acceptable salt thereof, wherein:

Q is a bond or optionally can be selected from O, NR⁷ or S(O)_(v), whenn* is an integer from 1 to 6;

Z is C═O or S(═O)₂;

R^(a) at each occurrence is independently selected from H, (C₁-C₃)alkyl,(halo)(C₁-C₃)alkyl, (hydroxy)(C₁-C₃)alkyl, (alkoxy)(C₁-C₃)alkyl, orcyano;

R^(b) is H, halo, (C₁-C₃)alkyl, (halo)(C₁-C₃)alkyl,(hydroxy)(C₁-C₃)alkyl, (alkoxy)(C₁-C₃)alkyl, or cyano;

R^(c) and R^(d) are independently selected from H, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, (halo)(C₁-C₃)alkyl, (halo)(C₁-C₃)alkoxy,(alkoxy)(C₁-C₃)alkyl, or (hydroxy)(C₁-C₃)alkyl, or R^(c) and R^(d) mayoptionally combine to form a spiro-cycloalkyl or heterocyclo ringsystem;

R^(e) is

-   -   (a) H or halo; or    -   (b) (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocyclo, cyano,        halogen, hydroxyl, —OR⁵, NR⁷R⁸, or heterocycloalkyl, any of        which may be optionally substituted with 1 or more R^(x) groups        as allowed by valence, or R^(e) and any one of the R′ or R″        groups may optionally combine to form a spiro-cycloalkyl or        heterocyclo ring system, or R^(d) and any one of the R′ or R″        groups may optionally combine to form a fused cycloalkyl or        heterocyclo ring system, or R^(d) and R^(e) may optionally        combine to form a fused cycloalkyl or heterocyclo ring system;

R′ and R″ at each occurrence, respectively, are independently H, halo,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, (halo)(C₁-C₃)alkyl, (halo)(C₁-C₃)alkoxy,(alkoxy)(C₁-C₃)alkyl, (hydroxy)(C₁-C₃)alkyl, —S—(C₁-C₃)alkyl,C(O)(C₁-C₃)alkyl, —NR⁷R⁸, or hydroxyl, or R′ and R″ bound to the samecarbon atom may optionally combine to form ═O, or R′ and R″ bound to thesame carbon atom may optionally combine to form a spiro-fused cycloalkylor heterocyclo ring system;

R¹ is

-   -   (a) —COOH, —C(O)OR¹⁰, —C(O)NHOH, —C(O)NH—NH₂, —C(O)NHS(O)₂R¹⁰,        —S(O)₂NHC(O)R¹⁰, —S(O)₂NR⁷R⁸, —NR⁷C(O)R¹⁰, —NR⁷C(O)OR⁵,        —C(O)NR⁷R⁸, —NR⁷S(O)₂R¹⁰, —R⁷C(O)NR⁷R⁸, —S(O)_(v)R¹⁰,        hydroxylalkyl, -cyclopropyl-COOH, or CN; or    -   (b) heteroaryl or heterocyclo, either of which may be optionally        independently substituted with one or more R^(x) groups as        allowed by valence;

R² is

-   -   (a) —NR⁷R⁸, NR⁷C(O)¹⁰, NR⁷C(O)NR⁷R¹⁰, or —C(R^(a))R⁵R⁶; or    -   (b) aryl, heteroaryl, cycloalkyl, or heterocyclo, any of which        may be optionally independently substituted with one or more        R^(x) groups as allowed by valence;

R³ and R⁴ are independently aryl or heteroaryl, either of which may beoptionally independently substituted with one or more R^(x) groups asallowed by valence, or either R³ and R^(a) together with the ring carbonatom to which they are both bonded, or R⁴ and R^(b) together with thering carbon atom to which they are both bonded may optionally combine toform a spiro-fused bicyclic ring system selected from

wherein K is —O—, —NR⁷—, or —C(═O)NR⁷—;

R⁵ and R⁶ at each occurrence, respectively, are independently selectedfrom

-   -   (a) H or CN;    -   (b) -(alkylene)_(t)-OH, -(alkylene)_(t)-OR⁹,        -(alkylene)_(t)-SR⁹, -(alkylene)_(t)-NR¹⁰R¹¹,        -(alkylene)_(t)-C(O)R⁹, -(alkylene)_(t)-C(O)OR⁹,        -(alkylene)_(t)-OC(O)R⁹, -(alkylene)_(t)-S(O)_(v)R⁹,        -(alkylene)_(t)-NHS(O)₂R¹⁰, -(alkylene)_(t)-N(R¹¹)S(O)₂R¹⁰,        -(alkylene)_(t)-S(O)₂NR¹⁰R¹¹, —NR¹⁰C(O)R⁹, C(O)NR¹⁰R¹¹,        NR¹⁰S(O)₂NR¹⁰, or NR¹⁰C(O)NR¹⁰R¹¹; or    -   (c) haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl,        C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, (C₃₋₈-cycloalkyl)(C₁₋₃alkyl),        C₄₋₈-cycloalkenyl, aryl, aryl(C₁₋₃-alkyl), heteroaryl,        heteroaryl(C₁₋₃-alkyl), heterocyclo or heterocyclo(C₁₋₃-alkyl),        any of which may be optionally independently substituted with        one or more R^(x) groups as allowed by valence;

R⁷ and R⁸ at each occurrence, respectively, are independently selectedfrom H, cyano, —OC₁₋₆-alkyl, C₁₋₆-alkyl, halo(C₁₋₆)-alkyl, cycloalkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,heteroarylalkyl, heterocyclo(C₁₋₁₀alkyl), or(C₃₋₈-cycloalkyl)(C₁₋₃alkyl), any of which may be optionally substitutedas allowed by valence with one or more R^(x), or R⁷ and R⁸ may combineto form a C₄-C₈-heterocyclo ring optionally substituted with one or moreR^(x);

R⁹ is haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, (C₃₋₈-cycloalkyl)(C₁₋₃alkyl), C₄₋₈-cycloalkenyl, aryl,heteroaryl, or heterocyclo, any of which may be optionally independentlysubstituted with one or more R^(x) groups as allowed by valence;

R¹⁰ and R¹¹ at each occurrence, respectively, are independently selectedfrom H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl,or cycloalkylalkyl, any of which may be optionally substituted asallowed by valence with one or more R^(x), or R¹⁰ and R¹¹ may combine toform a heterocyclo ring optionally substituted with one or more R^(x);

R^(x) at each occurrence is independently, deuterium, halo, cyano,nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(t)-OR*,-(alkylene)_(t)-S(O)_(v)R*, -(alkylene)_(t)-NR⁺R⁺⁺,-(alkylene)_(t)-C(═O)R*, -(alkylene)_(t)-C(═S)R*,-(alkylene)_(t)-C(═O)OR*, -(alkylene)_(t)-OC(═O)R*,-(alkylene)_(t)-C(═S)OR*, -(alkylene)_(t)-C(═O)NR⁺R⁺⁺,-(alkylene)_(t)-C(═S)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)C(═S)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)R*,-(alkylene)_(t)-N(R⁺)C(═S)R*, -(alkylene)_(t)-OC(═O)NR⁺R⁺⁺,-(alkylene)_(t)-OC(═S)NR⁺R⁺⁺, -(alkylene)_(t)-SO₂NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)SO₂R*, -(alkylene)_(t)-N(R⁺)SO₂NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)C(═O)OR*, -(alkylene)_(t)-N(R⁺)C(═S)OR*, or-(alkylene)_(t)-N(R⁺)SO₂R*, wherein said alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groupsmay be further independently substituted with one or more halo, cyano,oxo, -(alkylene)_(t)-OR*, -(alkylene)_(t)-S(O)_(v)R*,-(alkylene)_(t)-NR⁺R⁺⁺, -(alkylene)_(t)-C(═O)R*,-(alkylene)_(t)-C(═S)R*, -(alkylene)_(t)-C(═O)OR*,-(alkylene)_(t)-OC(═O)R*, -(alkylene)_(t)-C(═S)OR*,-(alkylene)_(t)-C(═O)NR⁺R⁺⁺, -(alkylene)_(t)-C(═S)NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)C(═O)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═S)NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)C(═O)R*, -(alkylene)_(t)-N(R⁺)C(═S)R*,-(alkylene)_(t)-OC(═O)NR⁺R⁺⁺, -(alkylene)_(t)-OC(═S)NR⁺R⁺⁺,-(alkylene)_(t)-SO₂NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)SO₂R*,-(alkylene)_(t)-N(R⁺)SO₂NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)OR*,-(alkylene)_(t)-N(R⁺)C(═S)OR*, or -(alkylene)_(t)-N(R⁺)SO₂R*;

R* is H, haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, aryl, heteroaryl, or heterocyclo;

R⁺ and R⁺⁺ are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl,heterocycloalkyl, or cycloalkylalkyl, or R⁺ and R⁺⁺ bound to the samenitrogen atom may optionally combine to form a heterocyclo ring system;

m is 1, 2 or 3;

n and n* are each independently selected from 0 or an integer from 1 to6;

p is 0, 1, 2 or 3;

t at each occurrence is independently 0 or an integer from 1 to 6; and

v at each occurrence is independently 0, 1 or 2.

In another aspect, aspect AA, the present invention provides compoundsof Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Q is a bond or optionally can be selected from O, NR⁷ or S(O)_(v), whenn* is an integer from 1 to 6;

Z is C═O or S(═O)₂;

R^(a) at each occurrence is independently selected from H, (C₁-C₃)alkyl,(halo)(C₁-C₃)alkyl, (hydroxy)(C₁-C₃)alkyl, (alkoxy)(C₁-C₃)alkyl, orcyano;

R^(b) is H, halo, (C₁-C₃)alkyl, (halo)(C₁-C₃)alkyl,(hydroxy)(C₁-C₃)alkyl, (alkoxy)(C₁-C₃)alkyl, or cyano;

R^(c) and R^(d) are independently selected from H, halo, (C₁-C₃)alkyl,(C₁-C₃)alkoxy, (halo)(C₁-C₃)alkyl, (halo)(C₁-C₃)alkoxy,(alkoxy)(C₁-C₃)alkyl, or (hydroxy)(C₁-C₃)alkyl, or R^(c) and R^(d) mayoptionally combine to form a spiro-cycloalkyl or heterocyclo ringsystem;

R^(e) is

-   -   (a) H or halo; or    -   (b) (C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, (C₃-C₈)heterocyclo, cyano,        halogen, hydroxyl, —OR⁵, NR⁷R⁸, or heterocycloalkyl, any of        which may be optionally substituted with 1 or more R^(x) groups        as allowed by valence, or R^(e) and any one of the R′ or R″        groups may optionally combine to form a spiro-cycloalkyl or        heterocyclo ring system, or R^(d) and any one of the R′ or R″        groups may optionally combine to form a fused cycloalkyl or        heterocyclo ring system, or R^(d) and R^(e) may optionally        combine to form a fused cycloalkyl or heterocyclo ring system;

R′ and R″ at each occurrence, respectively, are independently H, halo,(C₁-C₃)alkyl, (C₁-C₃)alkoxy, (halo)(C₁-C₃)alkyl, (halo)(C₁-C₃)alkoxy,(alkoxy)(C₁-C₃)alkyl, (hydroxy)(C₁-C₃)alkyl, —S—(C₁-C₃)alkyl,C(O)(C₁-C₃)alkyl, —NR⁷R⁸, or hydroxyl, or R′ and R″ bound to the samecarbon atom may optionally combine to form ═O, or R′ and R″ bound to thesame carbon atom may optionally combine to form a spiro-fused cycloalkylor heterocyclo ring system;

R¹ is

-   -   (a) —COOH, —C(O)OR¹⁰, —C(O)NHOH, —C(O)NH—NH₂, —C(O)NHS(O)₂R¹⁰,        —S(O)₂NHC(O)R¹⁰, —S(O)₂NR⁷R⁸, —NR⁷C(O)R¹⁰, —NR⁷C(O)OR⁵,        —C(O)NR⁷R⁸, —NR⁷S(O)₂R¹⁰, —NR⁷C(O)NR⁷R⁸, —S(O)_(v)R¹⁰,        hydroxylalkyl, -cyclopropyl-COOH, or CN; or    -   (b) heteroaryl or heterocyclo, either of which may be optionally        independently substituted with one or more R^(x) groups as        allowed by valence;

R² is

-   -   (a) —NR⁷R⁸, NR⁷C(O)OR¹⁰, NR⁷C(O)NR⁷R¹⁰, or —C(R^(a))R⁵R⁶; or    -   (b) aryl, heteroaryl, cycloalkyl, or heterocyclo, any of which        may be optionally independently substituted with one or more        R^(x) groups as allowed by valence;

R³ and R⁴ are independently aryl or heteroaryl, either of which may beoptionally independently substituted with one or more R^(x) groups asallowed by valence, or either R³ and R^(a) together with the ring carbonatom to which they are both bonded, or R⁴ and R^(b) together with thering carbon atom to which they are both bonded may optionally combine toform a spiro-fused bicyclic ring system selected from

wherein K is —O—, —NR⁷—, or —C(═O)NR⁷—;

R⁵ and R⁶ at each occurrence, respectively, are independently selectedfrom

-   -   (a) H or CN;    -   (b) -(alkylene)_(t)-OH, -(alkylene)_(t)-OR⁹,        -(alkylene)_(t)-SR⁹, -(alkylene)_(t)-NR¹⁰R¹¹,        -(alkylene)_(t)-C(O)R⁹, -(alkylene)_(t)-C(O)OR⁹,        -(alkylene)_(t)-OC(O)R⁹, -(alkylene)_(t)-S(O)_(v)R⁹,        -(alkylene)_(t)-NHS(O)₂R¹⁰, -(alkylene)_(t)-N(R¹¹)S(O)₂R¹⁰,        -(alkylene)_(t)-S(O)₂NR¹⁰R¹¹,        -(alkylene)_(t)-N(R¹¹)S(O)₂NR¹⁰R¹¹, —NR¹⁰C(O)R⁹, —C(O)NR¹⁰R¹¹,        —NR¹⁰S(O)₂R⁹, S(O)₂NR¹⁰, or NR¹⁰C(O)NR¹⁰R¹¹; or    -   (c) haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl,        C₂₋₆-alkynyl, C₃₋₈-cycloalkyl, (C₃₋₈-cycloalkyl)(C₁₋₃alkyl),        C₄₋₈-cycloalkenyl, aryl, aryl(C₁₋₃-alkyl), heteroaryl,        heteroaryl(C₁₋₃-alkyl), heterocyclo or heterocyclo(C₁₋₃-alkyl),        any of which may be optionally independently substituted with        one or more R^(x) groups as allowed by valence;

R⁷ and R⁸ at each occurrence, respectively, are independently selectedfrom H, cyano, —OC₁₋₆-alkyl, C₁₋₆-alkyl, halo(C₁₋₆)-alkyl, cycloalkyl,C₂₋₆-alkenyl, C₂₋₆-alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl,heteroarylalkyl, heterocyclo(C₁₋₁₀alkyl), or(C₃₋₈-cycloalkyl)(C₁₋₃alkyl), any of which may be optionally substitutedas allowed by valence with one or more R^(x), or R⁷ and R⁸ may combineto form a C₄-C₈-heterocyclo ring optionally substituted with one or moreR^(x);

R⁹ is haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, (C₃₋₈-cycloalkyl)(C₁₋₃alkyl), C₄₋₈-cycloalkenyl, aryl,heteroaryl, heterocyclo, or heterocycloalkyl, any of which may beoptionally independently substituted with one or more R^(x) groups asallowed by valence;

R¹⁰ and R¹¹ at each occurrence, respectively, are independently selectedfrom H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl,or cycloalkylalkyl, any of which may be optionally substituted asallowed by valence with one or more R^(x), or R¹⁰ and R¹¹ may combine toform a heterocyclo ring optionally substituted with one or more R^(x);

R^(x) at each occurrence is independently, deuterium, halo, cyano,nitro, oxo, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, heterocyclo, aryl, heteroaryl, arylalkyl, heteroarylalkyl,cycloalkylalkyl, heterocycloalkyl, -(alkylene)_(t)-OR*,-(alkylene)_(t)-S(O)_(v)R*, -(alkylene)_(t)-NR⁺R⁺⁺,-(alkylene)_(t)-C(═O)R*, -(alkylene)_(t)-C(═S)R*,-(alkylene)_(t)-C(═O)OR*, -(alkylene)_(t)-OC(═O)R*,-(alkylene)_(t)-C(═S)OR*, -(alkylene)_(t)-C(═O)NR⁺R⁺⁺,-(alkylene)_(t)-C(═S)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)C(═S)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)R*,-(alkylene)_(t)-N(R⁺)C(═S)R*, -(alkylene)_(t)-OC(═O)NR⁺R⁺⁺,-(alkylene)_(t)-OC(═S)NR⁺R⁺⁺, -(alkylene)_(t)-SO₂NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)SO₂R*, -(alkylene)_(t)-N(R⁺)SO₂NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)C(═O)OR*, -(alkylene)_(t)-N(R⁺)C(═S)OR*, or-(alkylene)_(t)-N(R⁺)SO₂R*, wherein said alkyl, haloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, heterocyclo, aryl, heteroaryl,arylalkyl, heteroarylalkyl, cycloalkylalkyl, and heterocycloalkyl groupsmay be further independently substituted with one or more halo, cyano,oxo, -(alkylene)_(t)-OR*, -(alkylene)_(t)-S(O)_(v)R*,-(alkylene)_(t)-NR⁺R⁺⁺, -(alkylene)_(t)-C(═O)R*,-(alkylene)_(t)-C(═S)R*, -(alkylene)_(t)-C(═O)OR*,-(alkylene)_(t)-OC(═O)R*, -(alkylene)_(t)-C(═S)OR*,-(alkylene)_(t)-C(═O)NR⁺R⁺⁺, -(alkylene)_(t)-C(═S)NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)C(═O)NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═S)NR⁺R⁺⁺,-(alkylene)_(t)-N(R⁺)C(═O)R*, -(alkylene)_(t)-N(R⁺)C(═S)R*,-(alkylene)_(t)-OC(═O)NR⁺R⁺⁺, -(alkylene)_(t)-OC(═S)NR⁺R⁺⁺,-(alkylene)_(t)-SO₂NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)SO₂R*,-(alkylene)_(t)-N(R⁺)SO₂NR⁺R⁺⁺, -(alkylene)_(t)-N(R⁺)C(═O)OR*,-(alkylene)_(t)-N(R⁺)C(═S)OR*, or -(alkylene)_(t)-N(R⁺)SO₂R*;

R* is H, haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, C₄₋₈-cycloalkenyl, aryl, heteroaryl, or heterocyclo;

R⁺ and R⁺⁺ are independently H, alkyl, haloalkyl, cycloalkyl, alkenyl,alkynyl, aryl, heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl,heterocycloalkyl, or cycloalkylalkyl, or R⁺ and R⁺⁺ bound to the samenitrogen atom may optionally combine to form a heterocyclo ring system;

m is 1, 2 or 3;

n and n* are each independently selected from 0 or an integer from 1 to6;

p is 0, 1, 2 or 3;

t at each occurrence is independently 0 or an integer from 1 to 6; and

v at each occurrence is independently 0, 1 or 2.

In another embodiment, embodiment 2, of the compounds of Aspect A or AA,or the pharmaceutically acceptable salts thereof, R² is —C(H)R⁵R⁶,—NR⁷R⁸, phenyl or pyridine, wherein the phenyl or the pyridyl may beoptionally substituted with one or more R^(x) as allowed by valence.

In another embodiment, embodiment 3, of the compounds of Aspect A or AA,or the pharmaceutically acceptable salts thereof, R² is selected from

-   -   any of which may be optionally substituted with one or more        R^(x) groups as allowed by valence.

In another embodiment, embodiment 4, the compounds of Aspect A or AAhave the structure of Formula IA

or the pharmaceutically acceptable salts thereof, wherein q and p areeach independently 0, 1, 2 or 3.

In another embodiment, embodiment 5, the compounds of Aspect A or AAhave the structure of Formula IB

or the pharmaceutically acceptable salts thereof, wherein q and p areeach independently 0, 1, 2 or 3.

In another embodiment, embodiment 6, the compounds of Aspect A or AAhave the structure of Formula IC

or the pharmaceutically acceptable salts thereof, wherein q and p areeach independently 0, 1, 2 or 3.

In another aspect of embodiment 6 (embodiment 7), or thepharmaceutically acceptable salts thereof, R² is selected from

-   -   any of which may be optionally substituted with one or more        R^(x) groups as allowed by valence.

In another aspect of embodiment 6 (embodiment 8) or the pharmaceuticallyacceptable salts thereof,

R² is selected from

-   -   any of which may be optionally substituted with one or more        R^(x) groups as allowed by valence;        and R¹ is

or a heteroaryl or heterocycle selected from

In another aspect of embodiment 6 (embodiment 9), or thepharmaceutically acceptable salts thereof,

R² is selected from

-   -   any of which may be optionally substituted with one or more        R^(x) groups as allowed by valence; and        R¹ is

or a heteroaryl or heterocycle selected from

In another aspect of embodiment 6 (embodiment 10), or thepharmaceutically acceptable salts thereof,

R² is selected from

-   -   any of which may be optionally substituted with one or more        R^(x) groups as allowed by valence; and        R¹ is

or a heteroaryl or heterocycle selected from

In another embodiment, embodiment 11, the compounds of Aspect A have thestructure of Formula ID

or a pharmaceutically acceptable salt thereof.

In another aspect of embodiment 11 (embodiment 12), or thepharmaceutically acceptable salts thereof, Re is H or methyl or ethyl.

In another embodiment, embodiment 13, the compounds of Aspect A have thestructure of Formula IE

or the pharmaceutically acceptable salts thereof.

In another aspect of embodiment 13 (embodiment 14), or thepharmaceutically acceptable salts thereof, Re is H or methyl or ethyl.

In another aspect of embodiment 13 (embodiment 15), or thepharmaceutically acceptable salts thereof, wherein

R² is selected from

-   -   any of which may be optionally substituted with one or more        R^(x) groups as allowed by valence; and        R¹ is

or a heteroaryl or heterocycle selected from

In another aspect of embodiment 13 (embodiment 16), or apharmaceutically acceptable salt thereof,

R¹ is

or a heteroaryl or heterocycle selected from

R² is

andR^(e) is methyl.

In another aspect of embodiment 13 (embodiment 17), or apharmaceutically acceptable salt thereof:

R² is

R⁵ is cyclopropyl, or C₁₋₆alkyl;R⁹ is haloalkyl, haloalkoxy, C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl,C₃₋₈-cycloalkyl, (C₃₋₈-cycloalkyl)(C₁₋₃alkyl), C₄₋₈-cycloalkenyl, aryl,heteroaryl, or heterocycloalkyl, or R⁹ is haloalkyl, haloalkoxy,C₁₋₆-alkyl, C₂₋₆alkenyl, C₂₋₆-alkynyl, C₃₋₈-cycloalkyl,(C₃₋₈-cycloalkyl)(C₁₋₃alkyl), C₄₋₈-cycloalkenyl, aryl, heteroaryl, orheterocyclo, any of which may be optionally independently substitutedwith one or more R^(x) groups as allowed by valence; andR¹⁰ and R¹¹ at each occurrence, respectively, are independently selectedfrom H, alkyl, haloalkyl, cycloalkyl, alkenyl, alkynyl, aryl,heteroaryl, heterocyclo, arylalkyl, heteroarylalkyl, heterocycloalkyl,or cycloalkylalkyl, any of which may be optionally substituted asallowed by valence with one or more R^(x), or R¹⁰ and R¹¹ may combine toform a heterocyclo ring optionally substituted with one or more R^(x).

In another aspect of embodiment 13 (embodiment 18), or apharmaceutically acceptable salt thereof,

R¹ is

R² is

and R^(e) is methyl.

In another aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, selected from:

-   2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-4-methyl-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5S,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-2-tert-Butoxy-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyclopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid (isomer 1);-   2-((3S,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic    acid (isomer 1);-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylamino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidothiomorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(thiazol-2-ylamino)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfonamido)    butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyridin-2-yl)pentan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(ethylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-ethylbutyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2,2-dimethylcyclopentyl)methyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclohexylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   Methyl    2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamide;-   Ethyl    2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetate;-   2-(2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)-N-hydroxyacetamide;-   (S)-Ethyl    2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-(methylsulfonamido)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate;-   (S)-Ethyl    2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-((3-morpholinopropyl)amino)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate;-   (3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one;-   (3R,5R,6S)-3-((1,3,4-oxadiazol-2-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one;-   (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-2-one;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamide;-   (3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one;-   (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methylisoxazol-3-yl)methyl)piperidin-2-one;-   2-((2′S,3′R,5′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)acetic    acid;-   2-((2′R,3′S,5′S)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((R)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclobutyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclopentyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one;-   5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,3,4-oxadiazol-2(3H)-one;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N-(trifluoromethylsulfonyl)acetamide;-   (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-pyrazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;-   (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxyisoxazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;-   5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)oxazolidine-2,4-dione;-   3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;-   3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;-   3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one;-   3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one;-   (3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfonylmethyl)-1-(pentan-3-yl)piperidin-2-one;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2,2-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-(2,6-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopropanecarbonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5,5-dimethyl-2-oxooxazolidin-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R,3S)-2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2R,3S)-2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,3′S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)acetic    acid;-   2-((3R,3′R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3S)-3-hydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3R)-3-hydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrazin-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   ((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)acetic    acid;-   ((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)acetic    acid;-   ((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)acetic    acid;-   ((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   2-((3R,5S,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid.-   In another aspect, the present invention provides a compound, or a    pharmaceutically acceptable salt thereof, selected from:-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic    acid;-   (S)-tert-butyl    2-((3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-5-oxohexan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S,5S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic    acid (isomer 1);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S,5R)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylmethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-6-methylheptan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic    acid (isomer 1);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-7-methyloctan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-cyclopropylmethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic    acid (isomer 1);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid (isomer 1);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(N-(2,2,2-trifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-cyano-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-2-oxopentan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3R)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3R)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-2-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-4-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-4-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(3S)-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3-hydroxypropyl)acetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-hydroxyethyl)acetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-hydroxyacetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-methoxyacetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N—((R)-2,3-dihydroxypropyl)acetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N—((S)-2,3-dihydroxypropyl)acetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-cyanoacetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-(dimethylamino)ethyl)acetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3,4-dihydroxybutyl)acetamide;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   (S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(3S)-2-(cyclopropanesulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid (isomer 1);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3S)-2-(cyclopropanesulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-(1-methylethylsulfonamido)pentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(neopentylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(N-(2,2,2-trifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dimethylethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2-dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-chlorophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4-methylphenylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-chlorophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methylphenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-methoxyphenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(phenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1-methylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-dimethyl-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-cyanophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyanophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridine-2-sulfonamido)butan-2-yl)piperidin-3-yl)acetic    acid.-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   3-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic    acid;-   3-((3R,5S,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-methyl-4-oxoheptan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(thiomorpholino-1,1-dioxide)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-difluoroazetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((2S)-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methyl(oxetan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxooxazolidin-3-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(pyridin-3-yloxy)butan-2-yl)piperidin-2-one;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic    acid (isomer 1);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-5-oxotetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic    acid (isomer 1);-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic    acid (isomer 2);-   2-((3R,5R,6S)-1-((R)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(3-methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(3-methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-chloropyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-chloropyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-cyclopropyl-1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-2-cyclopropyl-1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(6-methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(6-methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((R)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cyclopropylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-cyclopropylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-methyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-2-methyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   (3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;-   (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((R)-2,3-dihydroxypropyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one;-   (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((S)-2,3-dihydroxypropyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic    acid;-   2-((3R,5R,6S)-1-((S)-2-(tert-Butoxy)-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(1-methylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxy-4-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(pyridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(pyridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid.-   In another aspect, the present invention provides a compound, or a    pharmaceutically acceptable salt thereof, selected from:-   2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-4-methyl-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(2-tert-Butoxy-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxyethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methoxyethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((1-cyanocyclopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methoxyethoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-hydroxy-2-methylpropoxy)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylamino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(pyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidothiomorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(thiazol-2-ylamino)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(1-(1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(methylsulfonamido)    butan-2-yl)-2-oxopiperidin-3-yl)acetic acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(1-(pyridin-2-yl)pentan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)acetic;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-ethylbutyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2,2-dimethylcyclopentyl)methyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclohexylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   Methyl    2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamide;-   Ethyl    2-(2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetate;-   2-(2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)-N-hydroxyacetamide;-   Ethyl    2-(3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-(methylsulfonamido)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate;-   Ethyl    2-(3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-((3-morpholinopropyl)amino)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate;-   3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one;-   3-((1,3,4-oxadiazol-2-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-2-one;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamide.-   3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methylisoxazol-3-yl)methyl)piperidin-2-one;-   2-(6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-ethoxy-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethoxy)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclobutyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclopentyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one;-   5-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,3,4-oxadiazol-2(3H)-one;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N-(trifluoromethylsulfonyl)acetamide;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-pyrazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxyisoxazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;-   5-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)oxazolidine-2,4-dione;-   3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;-   3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;-   3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one;-   3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one;-   3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfonylmethyl)-1-(pentan-3-yl)piperidin-2-one;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2,2-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2,6-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-(cyclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-(cyclopropanecarbonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   3-((5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(5,5-dimethyl-2-oxooxazolidin-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3-hydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(tetrahydro-2H-pyran-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrazin-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   (4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)acetic    acid;-   (4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-(1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetic    acid;-   2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   2-(1-(1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid.-   In another aspect, the present invention provides a compound, or a    pharmaceutically acceptable salt thereof, selected from:-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic    acid;-   tert-butyl    2-(3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(5-oxohexan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxy-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylmethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(6-hydroxy-6-methylheptan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(7-hydroxy-7-methyloctan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-cyclopropylmethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(N-(2,2,2-trifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-hydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(5-cyano-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(2-oxopentan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-methoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxy-2-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(4-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-methoxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3-hydroxypropyl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-hydroxyethyl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-hydroxyacetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-methoxyacetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2,3-dihydroxypropyl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2,3-dihydroxypropyl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-cyanoacetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-(dimethylamino)ethyl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3,4-dihydroxybutyl)acetamide;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(2-(1-methylethylsulfonamido)pentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(neopentylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(N-(2,2,2-trifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dimethylethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,2-dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(1-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-ethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-chlorophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(4-methylphenylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-chlorophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(2-methylphenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-methoxyphenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(phenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1-methylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-dimethyl-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(4-cyanophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-cyanophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridine-2-sulfonamido)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,1-dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   3-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(6-methyl-4-oxoheptan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylmethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(1-(1-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(thiomorpholino-1,1-dioxide)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-difluoroazetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3,3-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methyl(oxetan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxooxazolidin-3-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)acetic    acid;-   3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(pyridin-3-yloxy)butan-2-yl)piperidin-2-one;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(5-oxotetrahydrofuran-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(1-(1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(3-methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-chloropyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-2-yl)butyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-cyclopropyl-1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-3-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyrazin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(6-methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(pyridin-4-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(1-(1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(thiazol-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-cyclopropylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(2-methyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-1-(2-hydroxypentan-3-yl)-3-methylpiperidin-2-one;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic    acid;-   2-(1-(2-(tert-Butoxy)-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(1-methylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxy-4-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropyl(pyridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid.-   In another aspect, the present invention provides a compound, or a    pharmaceutically acceptable salt thereof, selected from:-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dimethylethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2-dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid.-   In another aspect, the present invention provides a compound, or a    pharmaceutically acceptable salt thereof, selected from:-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dimethylethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,2-dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N,1-dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid.-   In another aspect, the present invention provides a compound, or a    pharmaceutically acceptable salt thereof, selected from:-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylthiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(5-chlorothiophene-2-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-2-(5-Chloro-N-methylthiophene-2-sulfonamido)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(difluoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(difluoromethyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(difluoromethyl)cyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   1-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(2-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(2-fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(3-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(2-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(propylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(3-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(pyridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(thiophen-2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(3-methoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyridin-2-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyridin-3-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(pyridin-2-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-ethylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-isopropylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(1-methylethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropanesulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylcyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(phenylsulfonyl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(propylsulfonyl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isobutylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclopropylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclobutylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopentylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(oxetan-3-ylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(((3-methyloxetan-3-yl)methyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-((tetrahydro-2H-pyran-4-yl)sulfonyl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-hydroxy-2-methylpropyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-((R)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-((S)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentylsulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(((3-methyloxetan-3-yl)methyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(phenylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(o-tolylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((4-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((4-fluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyridin-4-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-2-((2-Chloro-4-fluorophenyl)sulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((cyclopropylmethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(2,2,2-trifluoroethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((trifluoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(phenylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((2-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((3-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((4-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(propylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-2-(Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(isopentylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentylsulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclohexylsulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl-1-((2,2,2-trifluoroethyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)-3-methylbutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(ethylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(isopropylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutylsulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(isopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutylsulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(cyclopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(tert-pentylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((2,4-difluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(isopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(cyclopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pentan-3-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; more polar isomer;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3S)-2-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-((3-methyloxetan-3-yl)methyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-ylmethyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N,N-dimethylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-isopropylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(morpholinosulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(piperidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyrrolidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-2-(Azetidin-1-ylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((N,N-dimethylsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(3-methyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(3-isopropyl-2,2-dioxido-4-oxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   or    2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothiomorpholino)ethyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholino    ethyl)-2-oxopiperidin-3-yl)acetamide;-   2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholino    ethyl)-2-oxopiperidin-3-yl)acetamide;-   (1R,3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic    acid;-   (3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxopiperidin-3-yl)acetic    acid;-   (3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one;-   (3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one;-   (3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-one;-   (3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-one;-   (3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;-   (3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;-   (3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;-   (3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;-   (3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   (2S,3S,5S,6R,7aR,10aS)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dimethylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one.-   In another aspect, the present invention provides a compound, or a    pharmaceutically acceptable salt thereof, selected from:-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylthiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(5-chlorothiophene-2-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(2-(5-Chloro-N-methylthiophene-2-sulfonamido)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(difluoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(difluoromethyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(difluoromethyl)cyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   1-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(2-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(2-fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phenylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(3-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(N-(2-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(propylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(N-(3-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(pyridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(thiophen-2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(3-methoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-2-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-3-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-(pyridin-2-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-ethylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-isopropylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(1-methylethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclobutanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropanesulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-ethylcyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(phenylsulfonyl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-(propylsulfonyl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isobutylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((cyclopropylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((cyclobutylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopentylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(oxetan-3-ylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(((3-methyloxetan-3-yl)methyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(1-((tetrahydro-2H-pyran-4-yl)sulfonyl)butan-2-yl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-((2-hydroxy-2-methylpropyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentylsulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(((3-methyloxetan-3-yl)methyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(phenylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(o-tolylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((2-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((4-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((4-fluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyridin-4-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(2-((2-Chloro-4-fluorophenyl)sulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((cyclopropylmethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2,2,2-trifluoroethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((trifluoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(phenylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-((2-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((3-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((4-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(propylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(2-(Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopentylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclopentylsulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclohexylsulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-((2,2,2-trifluoroethyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(tert-Butylsulfonyl)-3-methylbutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(ethylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(1-(isopropylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclobutylsulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(cyclobutylsulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(cyclopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(tert-pentylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((2,4-difluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(isopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-((2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(cyclopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pentan-3-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(2-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(2-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-((3-methyloxetan-3-yl)methyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-(oxetan-3-ylmethyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-methylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N,N-dimethylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(N-isopropylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(morpholinosulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(piperidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(pyrrolidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(2-(Azetidin-1-ylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((N,N-dimethylsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3-methyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(3-isopropyl-2,2-dioxido-4-oxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(N-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(tert-Butylsulfonyl)butan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-(1-(isopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(1-(1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-(1-(cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-(morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothiomorpholino)ethyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholino    ethyl)-2-oxopiperidin-3-yl)acetamide;-   7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-(1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxopiperidin-3-yl)acetic    acid;-   5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one;-   5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-one;-   5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;-   5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-one;-   (5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dimethylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one.-   In another aspect, the present invention provides a compound, or a    pharmaceutically acceptable salt thereof, selected from:-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclopropylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid.

In another aspect, the present invention provides a compound, or apharmaceutically acceptable salt thereof, selected from:

-   2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-1-(-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(ethylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-((cyclopropylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid;-   2-(-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid; or-   2-(-1-(-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetic    acid.

The present invention provides pharmaceutical compositions comprising acompound of any one of the above aspects or embodiments, or apharmaceutically acceptable salt thereof, together with apharmaceutically acceptable excipient, diluent or carrier.

The present invention also provides method of treating cancer in asubject in need of said treatment, the method comprising administeringto the subject an effective dosage amount of a compound according to anyone of the above aspects or embodiments, or a pharmaceuticallyacceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “H” denotes a single hydrogen atom. This radical may beattached, for example, to an oxygen atom to form a hydroxyl radical.

Where the term “alkyl” is used, either alone or within other terms suchas “haloalkyl” or “alkylamino”, it embraces linear or branched radicalshaving one to about twelve carbon atoms. More preferred alkyl radicalsare “lower alkyl” radicals having one to about six carbon atoms.Examples of such radicals include methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and thelike. Even more preferred are lower alkyl radicals having one or twocarbon atoms. The term “alkylenyl” or “alkylene” embraces bridgingdivalent alkyl radicals such as methylenyl or ethylenyl. The term “loweralkyl substituted with R²” does not include an acetal moiety. The term“alkyl” further includes alkyl radicals wherein one or more carbon atomsin the chain is substituted with a heteroatom selected from oxygen,nitrogen, or sulfur.

The term “alkenyl” embraces linear or branched radicals having at leastone carbon-carbon double bond of two to about twelve carbon atoms. Morepreferred alkenyl radicals are “lower alkenyl” radicals having two toabout six carbon atoms. Most preferred lower alkenyl radicals areradicals having two to about four carbon atoms. Examples of alkenylradicals include ethenyl, propenyl, allyl, propenyl, butenyl and4-methylbutenyl. The terms “alkenyl” and “lower alkenyl”, embraceradicals having “cis” and “trans” orientations, or alternatively, “E”and “Z” orientations.

The term “alkynyl” denotes linear or branched radicals having at leastone carbon-carbon triple bond and having two to about twelve carbonatoms. More preferred alkynyl radicals are “lower alkynyl” radicalshaving two to about six carbon atoms. Most preferred are lower alkynylradicals having two to about four carbon atoms. Examples of suchradicals include propargyl, and butynyl, and the like.

Alkyl, alkylenyl, alkenyl, and alkynyl radicals may be optionallysubstituted with one or more functional groups such as halo, hydroxy,nitro, amino, cyano, haloalkyl, aryl, heteroaryl, and heterocyclo andthe like.

The term “halo” means halogens such as fluorine, chlorine, bromine oriodine atoms.

The term “haloalkyl” embraces radicals wherein any one or more of thealkyl carbon atoms is substituted with halo as defined above.Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkylradicals including perhaloalkyl. A monohaloalkyl radical, for example,may have either an iodo, bromo, chloro or fluoro atom within theradical. Dihalo and polyhaloalkyl radicals may have two or more of thesame halo atoms or a combination of different halo radicals. “Lowerhaloalkyl” embraces radicals having 1 to 6 carbon atoms. Even morepreferred are lower haloalkyl radicals having one to three carbon atoms.Examples of haloalkyl radicals include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl.

The term “perfluoroalkyl” means alkyl radicals having all hydrogen atomsreplaced with fluoro atoms. Examples include trifluoromethyl andpentafluoroethyl.

The term “hydroxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more hydroxyl radicals. More preferred hydroxyalkyl radicalsare “lower hydroxyalkyl” radicals having one to six carbon atoms and oneor more hydroxyl radicals. Examples of such radicals includehydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl andhydroxyhexyl. Even more preferred are lower hydroxyalkyl radicals havingone to three carbon atoms.

The term “alkoxy” embraces linear or branched oxy-containing radicalseach having alkyl portions of one to about ten carbon atoms. Morepreferred alkoxy radicals are “lower alkoxy” radicals having one to sixcarbon atoms. Examples of such radicals include methoxy, ethoxy,propoxy, butoxy and tert-butoxy. Even more preferred are lower alkoxyradicals having one to three carbon atoms. Alkoxy radicals may befurther substituted with one or more halo atoms, such as fluoro, chloroor bromo, to provide “haloalkoxy” radicals. Even more preferred arelower haloalkoxy radicals having one to three carbon atoms. Examples ofsuch radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy,trifluoroethoxy, fluoroethoxy and fluoropropoxy.

The term “aryl”, alone or in combination, means a carbocyclic aromaticsystem containing one or two rings, wherein such rings may be attachedtogether in a fused manner.

The term “aryl” embraces aromatic radicals such as phenyl, naphthyl,indenyl, tetrahydronaphthyl, and indanyl. More preferred aryl is phenyl.An “aryl” group may have 1 or more substituents such as lower alkyl,hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, and lower alkylamino,and the like. Phenyl substituted with —O—CH₂—O— forms the arylbenzodioxolyl substituent.

The term “heterocyclyl” (or “heterocyclo”) embraces saturated, partiallysaturated and unsaturated heteroatom-containing ring radicals, where theheteroatoms may be selected from nitrogen, sulfur and oxygen. It doesnot include rings containing —O—O—, —O—S— or —S—S— portions. The“heterocyclyl” group may have 1 to 4 substituents such as hydroxyl, Boc,halo, haloalkyl, cyano, lower alkyl, lower aralkyl, oxo, lower alkoxy,amino and lower alkylamino.

Examples of saturated heterocyclic radicals include saturated 3 to6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms[e.g., pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,piperazinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.,morpholinyl]; saturated 3 to 6-membered heteromonocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,thiazolidinyl]. Examples of partially saturated heterocyclyl radicalsinclude dihydrothienyl, dihydropyranyl, dihydrofuryl anddihydrothiazolyl.

Examples of unsaturated heterocyclic radicals, also termed “heteroaryl”radicals, include unsaturated 5 to 6 membered heteromonocyclyl groupcontaining 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl,pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl,pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl,2H-1,2,3-triazolyl]; unsaturated 5- to 6-membered heteromonocyclic groupcontaining an oxygen atom, for example, pyranyl, 2-furyl, 3-furyl, etc.;unsaturated 5 to 6-membered heteromonocyclic group containing a sulfuratom, for example, 2-thienyl, 3-thienyl, etc.; unsaturated 5- to6-membered heteromonocyclic group containing 1 to 2 oxygen atoms and 1to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl[e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl];unsaturated 5 to 6-membered heteromonocyclic group containing 1 to 2sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl,thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl].

The term heterocyclyl, (or heterocyclo) also embraces radicals whereheterocyclic radicals are fused/condensed with aryl radicals:unsaturated condensed heterocyclic group containing 1 to 5 nitrogenatoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl[e.g., tetrazolo[1,5-b]pyridazinyl]; unsaturated condensed heterocyclicgroup containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g.benzoxazolyl, benzoxadiazolyl]; unsaturated condensed heterocyclic groupcontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g.,benzothiazolyl, benzothiadiazolyl]; and saturated, partially unsaturatedand unsaturated condensed heterocyclic group containing 1 to 2 oxygen orsulfur atoms [e.g. benzofuryl, benzothienyl,2,3-dihydro-benzo[1,4]dioxinyl and dihydrobenzofuryl]. Preferredheterocyclic radicals include five to ten membered fused or unfusedradicals. More preferred examples of heteroaryl radicals includequinolyl, isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl,oxazolyl, furyl and pyrazinyl. Other preferred heteroaryl radicals are5- or 6-membered heteroaryl, containing one or two heteroatoms selectedfrom sulfur, nitrogen and oxygen, selected from thienyl, furyl,pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

Particular examples of non-nitrogen containing heteroaryl includepyranyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, benzofuryl, andbenzothienyl, and the like.

Particular examples of partially saturated and saturated heterocyclylinclude pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl,pyrazolidinyl, piperazinyl, morpholinyl, tetrahydropyranyl,thiazolidinyl, dihydrothienyl, 2,3-dihydro-benzo[1,4]dioxanyl,indolinyl, isoindolinyl, dihydrobenzothienyl, dihydrobenzofuryl,isochromanyl, chromanyl, 1,2-dihydroquinolyl,1,2,3,4-tetrahydro-isoquinolyl, 1,2,3,4-tetrahydro-quinolyl,2,3,4,4a,9,9a-hexahydro-1H-3-aza-fluorenyl,5,6,7-trihydro-1,2,4-triazolo[3,4-a]isoquinolyl,3,4-dihydro-2H-benzo[1,4]oxazinyl, benzo[1,4]dioxanyl,2,3-dihydro-1H-1λ′-benzo[d]isothiazol-6-yl, dihydropyranyl, dihydrofuryland dihydrothiazolyl, and the like.

The term “heterocyclo” thus encompasses the following ring systems:

and the like.

The term “sulfonyl”, whether used alone or linked to other terms such asalkylsulfonyl, denotes respectively divalent radicals —SO₂—.

The terms “sulfamyl,” “aminosulfonyl” and “sulfonamidyl,” denotes asulfonyl radical substituted with an amine radical, forming asulfonamide (—SO₂NH₂).

The term “alkylaminosulfonyl” includes “N-alkylaminosulfonyl” wheresulfamyl radicals are independently substituted with one or two alkylradical(s). More preferred alkylaminosulfonyl radicals are “loweralkylaminosulfonyl” radicals having one to six carbon atoms. Even morepreferred are lower alkylaminosulfonyl radicals having one to threecarbon atoms. Examples of such lower alkylaminosulfonyl radicals includeN-methylaminosulfonyl, and N-ethylaminosulfonyl.

The terms “carboxy” or “carboxyl,” whether used alone or with otherterms, such as “carboxyalkyl,” denotes —CO₂H.

The term “carbonyl,” whether used alone or with other terms, such as“aminocarbonyl,” denotes —(C═O)—.

The term “aminocarbonyl” denotes an amide group of the formula C(═O)NH₂.

The terms “N-alkylaminocarbonyl” and “N,N-dialkylaminocarbonyl” denoteaminocarbonyl radicals independently substituted with one or two alkylradicals, respectively.

More preferred are “lower alkylaminocarbonyl” having lower alkylradicals as described above attached to an aminocarbonyl radical.

The terms “N-arylaminocarbonyl” and “N-alkyl-N-arylaminocarbonyl” denoteaminocarbonyl radicals substituted, respectively, with one aryl radical,or one alkyl and one aryl radical.

The terms “heterocyclylalkylenyl” and “heterocyclylalkyl” embraceheterocyclic-substituted alkyl radicals. More preferredheterocyclylalkyl radicals are “5- or 6-membered heteroarylalkyl”radicals having alkyl portions of one to six carbon atoms and a 5- or6-membered heteroaryl radical. Even more preferred are lowerheteroarylalkylenyl radicals having alkyl portions of one to threecarbon atoms. Examples include such radicals as pyridylmethyl andthienylmethyl.

The term “aralkyl” embraces aryl-substituted alkyl radicals. Preferablearalkyl radicals are “lower aralkyl” radicals having aryl radicalsattached to alkyl radicals having one to six carbon atoms. Even morepreferred are “phenylalkylenyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include benzyl,diphenylmethyl and phenylethyl. The aryl in said aralkyl may beadditionally substituted with halo, alkyl, alkoxy, halkoalkyl andhaloalkoxy.

The term “alkylthio” embraces radicals containing a linear or branchedalkyl radical, of one to ten carbon atoms, attached to a divalent sulfuratom. Even more preferred are lower alkylthio radicals having one tothree carbon atoms. An example of “alkylthio” is methylthio, (CH₃S—).

The term “haloalkylthio” embraces radicals containing a haloalkylradical, of one to ten carbon atoms, attached to a divalent sulfur atom.Even more preferred are lower haloalkylthio radicals having one to threecarbon atoms. An example of “haloalkylthio” is trifluoromethylthio.

The term “alkylamino” embraces “N-alkylamino” and “N,N-dialkylamino”where amino groups are independently substituted with one alkyl radicaland with two alkyl radicals, respectively. More preferred alkylaminoradicals are “lower alkylamino” radicals having one or two alkylradicals of one to six carbon atoms, attached to a nitrogen atom. Evenmore preferred are lower alkylamino radicals having one to three carbonatoms. Suitable alkylamino radicals may be mono or dialkylamino such asN-methylamino, N-ethylamino, N,N-dimethylamino, and N,N-diethylamino,and the like.

The term “arylamino” denotes amino groups, which have been substitutedwith one or two aryl radicals, such as N-phenylamino. The arylaminoradicals may be further substituted on the aryl ring portion of theradical.

The term “heteroarylamino” denotes amino groups, which have beensubstituted with one or two heteroaryl radicals, such as N-thienylamino.The “heteroarylamino” radicals may be further substituted on theheteroaryl ring portion of the radical.

The term “aralkylamino” denotes amino groups, which have beensubstituted with one or two aralkyl radicals. More preferred arephenyl-C₁-C₃-alkylamino radicals, such as N-benzylamino. Thearalkylamino radicals may be further substituted on the aryl ringportion.

The terms “N-alkyl-N-arylamino” and “N-aralkyl-N-alkylamino” denoteamino groups, which have been independently substituted with one aralkyland one alkyl radical, or one aryl and one alkyl radical, respectively,to an amino group.

The term “aminoalkyl” embraces linear or branched alkyl radicals havingone to about ten carbon atoms any one of which may be substituted withone or more amino radicals. More preferred aminoalkyl radicals are“lower aminoalkyl” radicals having one to six carbon atoms and one ormore amino radicals. Examples of such radicals include aminomethyl,aminoethyl, aminopropyl, aminobutyl and aminohexyl. Even more preferredare lower aminoalkyl radicals having one to three carbon atoms.

The term “alkylaminoalkyl” embraces alkyl radicals substituted withalkylamino radicals. More preferred alkylaminoalkyl radicals are “loweralkylaminoalkyl” radicals having alkyl radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkyl radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkylradicals may be mono or dialkyl substituted, such asN-methylaminomethyl, N,N-dimethyl-aminoethyl, andN,N-diethylaminomethyl, and the like.

The term “alkylaminoalkoxy” embraces alkoxy radicals substituted withalkylamino radicals. More preferred alkylaminoalkoxy radicals are “loweralkylaminoalkoxy” radicals having alkoxy radicals of one to six carbonatoms. Even more preferred are lower alkylaminoalkoxy radicals havingalkyl radicals of one to three carbon atoms. Suitable alkylaminoalkoxyradicals may be mono or dialkyl substituted, such asN-methylaminoethoxy, N,N-dimethylaminoethoxy, andN,N-diethylaminoethoxy, and the like.

The term “alkylaminoalkoxyalkoxy” embraces alkoxy radicals substitutedwith alkylaminoalkoxy radicals. More preferred alkylaminoalkoxyalkoxyradicals are “lower alkylaminoalkoxyalkoxy” radicals having alkoxyradicals of one to six carbon atoms. Even more preferred are loweralkylaminoalkoxyalkoxy radicals having alkyl radicals of one to threecarbon atoms. Suitable alkylaminoalkoxyalkoxy radicals may be mono ordialkyl substituted, such as N-methylaminomethoxyethoxy,N-methylaminoethoxyethoxy, N,N-dimethylaminoethoxyethoxy, andN,N-diethylaminomethoxymethoxy, and the like.

The term “carboxyalkyl” embraces linear or branched alkyl radicalshaving one to about ten carbon atoms any one of which may be substitutedwith one or more carboxy radicals. More preferred carboxyalkyl radicalsare “lower carboxyalkyl” radicals having one to six carbon atoms and onecarboxy radical. Examples of such radicals include carboxymethyl, andcarboxypropyl, and the like. Even more preferred are lower carboxyalkylradicals having one to three CH₂ groups.

The term “halosulfonyl” embraces sulfonyl radicals substituted with ahalogen radical. Examples of such halosulfonyl radicals includechlorosulfonyl and fluorosulfonyl.

The term “arylthio” embraces aryl radicals of six to ten carbon atoms,attached to a divalent sulfur atom. An example of “arylthio” isphenylthio.

The term “aralkylthio” embraces aralkyl radicals as described above,attached to a divalent sulfur atom. More preferred arephenyl-C₁-C₃-alkylthio radicals. An example of “aralkylthio” isbenzylthio.

The term “aryloxy” embraces optionally substituted aryl radicals, asdefined above, attached to an oxygen atom. Examples of such radicalsinclude phenoxy.

The term “aralkoxy” embraces oxy-containing aralkyl radicals attachedthrough an oxygen atom to other radicals. More preferred aralkoxyradicals are “lower aralkoxy” radicals having optionally substitutedphenyl radicals attached to lower alkoxy radical as described above.

The term “heteroaryloxy” embraces optionally substituted heteroarylradicals, as defined above, attached to an oxygen atom.

The term “heteroarylalkoxy” embraces oxy-containing heteroarylalkylradicals attached through an oxygen atom to other radicals. Morepreferred heteroarylalkoxy radicals are “lower heteroarylalkoxy”radicals having optionally substituted heteroaryl radicals attached tolower alkoxy radical as described above.

The term “cycloalkyl” includes saturated carbocyclic groups. Preferredcycloalkyl groups include C₃-C₆ rings. More preferred compounds include,cyclopentyl, cyclopropyl, and cyclohexyl.

The term “cycloalkylalkyl” embraces cycloalkyl-substituted alkylradicals. Preferable cycloalkylalkyl radicals are “lowercycloalkylalkyl” radicals having cycloalkyl radicals attached to alkylradicals having one to six carbon atoms. Even more preferred are “5 to6-membered cycloalkylalkyl” attached to alkyl portions having one tothree carbon atoms. Examples of such radicals include cyclohexylmethyl.The cycloalkyl in said radicals may be additionally substituted withhalo, alkyl, alkoxy and hydroxy.

The term “cycloalkenyl” includes carbocyclic groups having one or morecarbon-carbon double bonds including “cycloalkyldienyl” compounds.Preferred cycloalkenyl groups include C₃-C₆ rings. More preferredcompounds include, for example, cyclopentenyl, cyclopentadienyl,cyclohexenyl and cycloheptadienyl.

The term “comprising” is meant to be open ended, including the indicatedcomponent but not excluding other elements.

A group or atom that replaces a hydrogen atom is also called asubstituent.

Any particular molecule or group can have one or more substituentdepending on the number of hydrogen atoms that can be replaced.

The symbol “—” represents a covalent bond and can also be used in aradical group to indicate the point of attachment to another group. Inchemical structures, the symbol is commonly used to represent a methylgroup in a molecule.

The term “therapeutically effective amount” means an amount of acompound that ameliorates, attenuates or eliminates one or more symptomof a particular disease or condition, or prevents or delays the onset ofone of more symptom of a particular disease or condition.

The terms “patient” and “subject” may be used interchangeably and meananimals, such as dogs, cats, cows, horses, sheep and humans. Particularpatients are mammals. The term patient includes males and females.

The term “pharmaceutically acceptable” means that the referencedsubstance, such as a compound of Formula I, or a salt of a compound ofFormula I, or a formulation containing a compound of Formula I, or aparticular excipient, are suitable for administration to a patient.

The terms “treating”, “treat” or “treatment” and the like includepreventative (e.g., prophylactic) and palliative treatment.

The term “excipient” means any pharmaceutically acceptable additive,carrier, diluent, adjuvant, or other ingredient, other than the activepharmaceutical ingredient (API), which is typically included forformulation and/or administration to a patient.

The compounds of the present invention are administered to a patient ina therapeutically effective amount. The compounds can be administeredalone or as part of a pharmaceutically acceptable composition orformulation. In addition, the compounds or compositions can beadministered all at once, as for example, by a bolus injection, multipletimes, such as by a series of tablets, or delivered substantiallyuniformly over a period of time, as for example, using transdermaldelivery. It is also noted that the dose of the compound can be variedover time.

In addition, the compounds of the present invention can be administeredalone, in combination with other compounds of the present invention, orwith other pharmaceutically active compounds. The other pharmaceuticallyactive compounds can be intended to treat the same disease or conditionas the compounds of the present invention or a different disease orcondition. If the patient is to receive or is receiving multiplepharmaceutically active compounds, the compounds can be administeredsimultaneously, or sequentially. For example, in the case of tablets,the active compounds may be found in one tablet or in separate tablets,which can be administered at once or sequentially in any order. Inaddition, it should be recognized that the compositions may be differentforms. For example, one or more compound may be delivered via a tablet,while another is administered via injection or orally as a syrup. Allcombinations, delivery methods and administration sequences arecontemplated.

The term “cancer” means a physiological condition in mammals that ischaracterized by unregulated cell growth. General classes of cancersinclude carcinomas, lymphomas, sarcomas, and blastomas.

The compounds of the present invention can be used to treat cancer. Themethods of treating a cancer comprise administering to a patient in needthereof a therapeutically effective amount of a compound of Formula I,IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof.

The compounds of the present invention can be used to treat tumors. Themethods of treating a tumor comprise administering to a patient in needthereof a therapeutically effective amount of a compound of Formula I,IA, IB, IC, ID or IE, or a pharmaceutically acceptable salt thereof.

The invention also concerns the use of a compound of the presentinvention in the manufacture of a medicament for the treatment of acondition such as a cancer. Cancers which may be treated with compoundsof the present invention include, without limitation, carcinomas such ascancer of the bladder, breast, colon, rectum, kidney, liver, lung (smallcell lung cancer, and non-small-cell lung cancer), esophagus,gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, andskin (including squamous cell carcinoma); hematopoietic tumors oflymphoid lineage (including leukemia, acute lymphocytic leukemia,chronic myelogenous leukemia, acute lymphoblastic leukemia, B-celllymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma,hairy cell lymphoma and Burkett's lymphoma); hematopoietic tumors ofmyeloid lineage (including acute and chronic myelogenous leukemias,myelodysplastic syndrome and promyelocytic leukemia); tumors ofmesenchymal origin (including fibrosarcoma and rhabdomyosarcoma, andother sarcomas, e.g., soft tissue and bone); tumors of the central andperipheral nervous system (including astrocytoma, neuroblastoma, gliomaand schwannomas); and other tumors (including melanoma, seminoma,teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma,thyroid follicular cancer and Kaposi's sarcoma). Other cancers that canbe treated with a compound of the present invention include endometrialcancer, head and neck cancer, glioblastoma, malignant ascites, andhematopoietic cancers.

Particular cancers that can be treated by the compounds of the presentinvention include soft tissue sarcomas, bone cancers such asosteosarcoma, breast tumors, bladder cancer, Li-Fraumeni syndrome, braintumors, rhabdomyosarcoma, adrenocortical carcinoma, colorectal cancer,non-small cell lung cancer, and acute myeleogenous leukemia (AML).

In a particular embodiment of the invention that relates to thetreatment of cancers, the cancer is identified as p53wildtype(p53^(WT)). In another particular embodiment, the cancer is identifiedas p53^(WT) and CDKN2A mutant. In another aspect, the present inventionprovides a diagnostic for determining which patients should beadministered a compound of the present invention. For example, a sampleof a patient's cancer cells may be taken and analyzed to determine thestatus of the cancer cells with respect to p53 and/or CDKN2A. In oneaspect, a patient having a cancer that is p53^(WT) will be selected fortreatment over patients having a cancer that is mutated with respect top53. In another aspect, a patient having a cancer that is both p53^(WT)and has a mutant CDNK2A protein is selected over a patient that does nothave these characteristics. The taking of a cancer cells for analyses iswell known to those skilled in the art. The term “p53^(WT)” means aprotein encoded by genomic DNA sequence no. NC_(—)000017 version 9(7512445.7531642)(GenBank); a protein encoded by cDNA sequence no.NM_(—)000546 (GenBank); or a protein having the GenBank sequence no.NP_(—)000537.3. The term “CDNK2A mutant” means a CDNK2A protein that innot wildtype. The term “CDKN2A wildtype” means a protein encoded bygenomic DNA sequence no. 9:21957751-21984490 (Ensembl ID); a proteinencoded by cDNA sequence no. NM_(—)000077 (GenBank) or NM_(—)0581959GenBank) or; or a protein having the GenBank sequence no. NP_(—)000068or NP_(—)478102.

The compounds of the present invention can also be used to treathyperproliferative disorders such as thyroid hyperplasia (especiallyGrave's disease), and cysts (such as hypervascularity of ovarian stroma,characteristic of polycystic ovarian syndrome (Stein-Leventhalsyndrome)).

The compounds of the present invention can also be used to treat thefollowing diseases or conditions: asthma, chronic obstructive pulmonarydisease (COPD), emphysema, psoriasis, contact dermatitis,conjunctivitis, allergic rhinitis, systemic lupus erythematosus (SLE),ulcerative colitis, Crohn's disease, multiple sclerosis, rheumatoidarthritis, inflammatory bowel disease, Alzheimer's disease,atherosclerosis and Huntington's disease.

The compounds of the present invention can also be used to treatinflammatory diseases, hypoxia, ulcers, viral infections, bacterialinfections, and bacterial sepsis.

The compounds of Formula I, IA, IB, IC, ID or IE, or thepharmaceutically acceptable salts thereof, may also be administered incombination with one or more additional pharmaceutically activecompounds/agents. In a particular embodiment, the additionalpharmaceutically active agent is an agent that can be used to treat acancer. For example, an additional pharmaceutically active agent can beselected from antineoplastic agents, anti-angiogenic agents,chemotherapeutic agents and peptidal cancer therapy agents. In yetanother embodiment, the antineoplastic agents are selected fromantibiotic-type agents, alkylating agents, antimetabolite agents,hormonal agents, immunological agents, interferon-type agents, kinaseinhibitors, miscellaneous agents and combinations thereof. It is notedthat the additional pharmaceutically active compounds/agents may be atraditional small organic chemical molecules or can be macromoleculessuch as a proteins, antibodies, peptibodies, DNA, RNA or fragments ofsuch macromolecules.

Examples of specific pharmaceutically active agents that can be used inthe treatment of cancers and that can be used in combination with one ormore compound of the present invention include: methotrexate; tamoxifen;fluorouracil; 5-fluorouracil; hydroxyurea; mercaptopurine; cisplatin;carboplatin; daunorubicin; doxorubicin; etoposide; vinblastine;vincristine; pacitaxel; thioguanine; idarubicin; dactinomycin; imatinib;gemcitabine; altretamine; asparaginase; bleomycin; capecitabine;carmustine; cladisat. aq. NaCl solution; cyclophosphamine; cytarabine;decarazine; docetaxel; idarubicin; ifosfamide; irinotecan; fludarabine;mitosmycin; mitoxane; mitoxantrone; topotecan; vinorelbine; adriamycin;mithram; imiquimod; alemtuzmab; exemestane; bevacizumab; cetuximab;azacitidine; clofarabine; decitabine; desatinib; dexrazoxane; docetaxel;epirubicin; oxaliplatin; erlotinib; raloxifene; fulvestrant; letrozole;gefitinib; gemtuzumab; trastuzumab; gefitinib; ixabepilone; lapatinib;lenalidomide; aminolevulinic acid; temozolomide; nelarabine; sorafenib;nilotinib; pegaspargase; pemetrexed; rituximab; dasatinib; thalidomide;bexarotene; temsirolimus; bortezomib; vorinostat; capecitabine;zoledronic acid; anastrozole; sunitinib; aprepitant and nelarabine, or apharmaceutically acceptable salt thereof.

Additional pharmaceutically active agents that can be used in thetreatment of cancers and that can be used in combination with one ormore compound of the present invention include: vascular endothelialgrowth factor (VEGF) inhibitors, hepatocyte growth factor/scatter factor(HGF/SF) inhibitors, angiopoietin 1 and/or 2 inhibitors, tumor necrosisfactor-related apoptosis-inducing ligand (TRAIL) agonists, recombinanthuman apo2 ligand (TRAIL), insulin-like growth factor 1 receptor(IGFR-1) inhibitors, cFMS inhibitors, HER 2 inhibitors, c-metinhibitors, aurora kinase inhibitors, CDK 4 and/or 6 inhibitors, andB-raf inhibitors.

Further additional pharmaceutically active agents that can be used inthe treatment of cancers and that can be used in combination with one ormore compound of the present invention include antibody drug conjugates(ADCs) whereby an antibody that binds to a protein, preferably on acancer cell, is conjugated using a linker with a chemical compound thatis detrimental to the cancer cell. Examples of chemical compounds thatare detrimental to a cancer cell include maytansinoids derivatives andauristatin derivatives.

Still further additional pharmaceutically active agents that can be usedin the treatment of cancers and that can be used in combination with oneor more compound of the present invention include: epoetin alfa;darbepoetin alfa; panitumumab; pegfilgrastim; palifermin; filgrastim;denosumab; ancestim; AMG 102; AMG 319; AMG 386; AMG 479 (Ganitumab); AMG511, AMG 900, AMG 655 (Conatumumab); AMG 745; AMG 951; and AMG 706(Motesanib), or a pharmaceutically acceptable salt thereof.

In another aspect, the present invention relates to the use of thecompounds of the present invention in combination with one or morepharmaceutical agent that is an inhibitor of a protein in thephosphatidylinositol 3-kinase (PI3K) pathway. Combinations of compoundsof the present invention along with inhibitors of proteins in the PI3Kpathway have shown synergy in cancer cell growth assays, includingenhanced apoptosis and cell killing. Examples of proteins in the PI3Kpathway include PI3K, mTOR and PKB (also known as Akt). The PI3K proteinexists in several isoforms including α, β, δ, or γ. It is contemplatedthat a PI3K inhibitor that can be used in combination with a compound ofthe present invention can be selective for one or more isoform. Byselective it is meant that the compounds inhibit one or more isoformmore that other isoforms. Selectivity is a concept well known to thoseis the art and can be measured with well known activity in vitro orcell-based assays. Preferred selectivity includes greater than 2 fold,preferably 10 fold, or more preferably 100 fold greater selectivity forone or more isoform over the other isoforms. In one aspect, the PI3Kinhibitors that can be used in combination with compounds of the presentinvention is a PI3K a selective inhibitor. In another aspect thecompound is a PI3K δ selective inhibitor.

Examples of PI3K inhibitors that can be used in combination with one ormore compounds of the present invention include those disclosed in thefollowing: PCT published application no. WO2010/151791; PCT publishedapplication no. WO2010/151737; PCT published application no.WO2010/151735; PCT published application no. WO2010151740; PCT publishedapplication no. WO2008/118455; PCT published application no.WO2008/118454; PCT published application no. WO2008/118468; U.S.published application no. US20100331293; U.S. published application no.US20100331306; U.S. published application no. US20090023761; U.S.published application no. US20090030002; U.S. published application no.US20090137581; U.S. published application no. US2009/0054405; U.S.published application no. U.S. 2009/0163489; U.S. published applicationno. US 2010/0273764; U.S. published application no. U.S. 2011/0092504;or PCT published application no. WO2010/108074.

Preferred PI3K inhibitors for use in combination with compounds of thepresent invention include:

or a pharmaceutically acceptable salt thereof.

Also preferred is a compound of Formula IIa below, or a pharmaceuticallyacceptable salt thereof,

wherein X¹ is fluorine or hydrogen; Y¹ is hydrogen or methyl; and Z¹ ishydrogen or methyl.

Compounds that inhibit both PI3K and mTOR (dual inhibitors) are known.In still another aspect, the present invention provides the use of dualPI3K and mTOR inhibitors for use in combination with a compound of thepresent invention.

mTOR is a protein in the PI3K pathway. It is another aspect of thepresent invention to use an mTOR inhibitor in combination with one ormore compounds of the present invention. mTOR inhibitors that can beused in combination with compounds of the present invention includethose disclosed in the following documents: PCT published applicationno. WO2010/132598 or PCT published application no. WO2010/096314.

PKB (Akt) is also a protein in the PI3K pathway. It is another aspect ofthe present invention to use an mTOR inhibitor in combination with oneor more compounds of the present invention. PKB inhibitors that can beused in combination with compounds of the present invention includethose disclosed in the following documents: U.S. Pat. Nos. 7,354,944;7,700,636; 7,919,514; 7,514,566; U.S. patent application publication no.US 2009/0270445 A1; U.S. Pat. No. 7,919,504; U.S. Pat. No. 7,897,619; orPCT published application no. WO 2010/083246 A1.

The compounds of the present invention can be used in combination withCDK4 and/or 6 inhibitors. CDK 4 and/or 6 inhibitors that can be used incombination with compounds of the present invention include thosedisclosed in the following documents: PCT published application no. WO2009/085185 or U.S. patent application publication no. US2011/0097305.

The compounds of the present invention can also be used in combinationwith pharmaceutically active agents that treat nausea. Examples ofagents that can be used to treat nausea include: dronabinol;granisetron; metoclopramide; ondansetron; and prochlorperazine; or apharmaceutically acceptable salt thereof.

In addition, the compounds of the present invention can be used incombination with other agents that can be used to treat cancer such asacemannan; aclarubicin; aldesleukin; alitretinoin; amifostine;amrubicin; amsacrine; anagrelide; arglabin; arsenic trioxide; BAM 002(Novelos); bicalutamide; broxuridine; celmoleukin; cetrorelix;cladribine; clotrimazole; DA 3030 (Dong-A); daclizumab; denileukindiftitox; deslorelin; dilazep; docosanol; doxercalciferol;doxifluridine; bromocriptine; cytarabine; HIT diclofenac; interferonalfa; tretinoin; edelfosine; edrecolomab; eflornithine; emitefur;epirubicin; epoetin beta; etoposide phosphate; exisulind; fadrozole;finasteride; fludarabine phosphate; formestane; fotemustine; galliumnitrate; gemtuzumab zogamicin; gimeracil/oteracil/tegafur combination;glycopine; goserelin; heptaplatin; human chorionic gonadotropin; humanfetal alpha fetoprotein; ibandronic acid; interferon alfa; interferonalfa natural; interferon alfa-2; interferon alfa-2a; interferon alfa-2b;interferon an-N1; interferon alfa-n3; interferon alfacon-1; interferonalpha natural; interferon beta; interferon beta-1a; interferon beta-1b;interferon gamma natural; interferon gamma-1a; interferon gamma-1b;interleukin-1 beta; iobenguane; irsogladine; lanreotide; LC 9018(Yakult); leflunomide; lenograstim; lentinan sulfate; letrozole;leukocyte alpha interferon; leuprorelin; levamisole+fluorouracil;liarozole; lobaplatin; lonidamine; lovastatin; masoprocol; melarsoprol;metoclopramide; mifepristone; miltefosine; mirimostim; mismatched doublestranded RNA; mitoguazone; mitolactol; mitoxantrone; molgramostim;nafarelin; naloxone+pentazocine; nartograstim; nedaplatin; nilutamide;noscapine; novel erythropoiesis stimulating protein; NSC 631570octreotide; oprelvekin; osaterone; paclitaxel; pamidronic acid;peginterferon alfa-2b; pentosan polysulfate sodium; pentostatin;picibanil; pirarubicin; rabbit antithymocyte polyclonal antibody;polyethylene glycol interferon alfa-2a; porfimer sodium; raltitrexed;rasburicase; rhenium Re 186 etidronate; RII retinamide; romurtide;samarium (153 Sm) lexidronam; sargramostim; sizofuran; sobuzoxane;sonermin; strontium-89 chloride; suramin; tasonermin; tazarotene;tegafur; temoporfin; teniposide; tetrachlorodecaoxide; thymalfasin;thyrotropin alfa; toremifene; tositumomab-iodine 131; treosulfan;tretinoin; trilostane; trimetrexate; triptorelin; tumor necrosis factoralpha natural; ubenimex; bladder cancer vaccine; Maruyama vaccine;melanoma lysate vaccine; valrubicin; verteporfin; virulizin; zinostatinstimalamer; abarelix; AE 941 (Aeterna); ambamustine; antisenseoligonucleotide; bcl-2 (Genta); APC 8015 (Dendreon);dexaminoglutethimide; diaziquone; EL 532 (Elan); EM 800 (Endorecherche);eniluracil; etanidazole; fenretinide; filgrastim SDO1 (Amgen);galocitabine; gastrin 17 immunogen; HLA-B7 gene therapy (Vical);granulocyte macrophage colony stimulating factor; histaminedihydrochloride; ibritumomab tiuxetan; ilomastat; IM 862 (Cytran);interleukin-2; iproxifene; LDI 200 (Milkhaus); leridistim; lintuzumab;CA 125 monoclonal antibody (MAb) (Biomira); cancer MAb (JapanPharmaceutical Development); HER-2 and Fc MAb (Medarex); idiotypic105AD7 MAb (CRC Technology); idiotypic CEA MAb (Trilex); LYM-1-iodine131 MAb (Techniclone); polymorphic epithelial mucin-yttrium 90 MAb(Antisoma); marimastat; menogaril; mitumomab; motexafin gadolinium; MX 6(Galderma); nolatrexed; P 30 protein; pegvisomant; porfiromycin;prinomastat; RL 0903 (Shire); rubitecan; satraplatin; sodiumphenylacetate; sparfosic acid; SRL 172 (SR Pharma); SU 5416 (Pfizer); TA077 (Tanabe); tetrathiomolybdate; thaliblastine; thrombopoietin; tinethyl etiopurpurin; tirapazamine; cancer vaccine (Biomira); melanomavaccine (New York University); melanoma vaccine (Sloan KetteringInstitute); melanoma oncolysate vaccine (New York Medical College);viral melanoma cell lysates vaccine (Royal Newcastle Hospital); orvalspodar. It is noted that the agents recited above may also beadministered as pharmaceutically acceptable salts when appropriate.

The compounds of the present invention may also be used in combinationwith radiation therapy, hormone therapy, surgery and immunotherapy,which therapies are well known to those skilled in the art.

Since one aspect of the present invention contemplates the treatment ofthe disease/conditions with a combination of pharmaceutically activecompounds that may be administered separately, the invention furtherrelates to combining separate pharmaceutical compositions in kit form.The kit comprises two separate pharmaceutical compositions: a compoundof the present invention, and a second pharmaceutical compound. The kitcomprises a container for containing the separate compositions such as adivided bottle or a divided foil packet. Additional examples ofcontainers include syringes, boxes and bags. Typically, the kitcomprises directions for the use of the separate components. The kitform is particularly advantageous when the separate components arepreferably administered in different dosage forms (e.g., oral andparenteral), are administered at different dosage intervals, or whentitration of the individual components of the combination is desired bythe prescribing physician or veterinarian.

An example of such a kit is a so-called blister pack. Blister packs arewell known in the packaging industry and are being widely used for thepackaging of pharmaceutical unit dosage forms (tablets, capsules, andthe like). Blister packs generally consist of a sheet of relativelystiff material covered with a foil of a preferably transparent plasticmaterial. During the packaging process recesses are formed in theplastic foil. The recesses have the size and shape of the tablets orcapsules to be packed. Next, the tablets or capsules are placed in therecesses and the sheet of relatively stiff material is sealed againstthe plastic foil at the face of the foil which is opposite from thedirection in which the recesses were formed. As a result, the tablets orcapsules are sealed in the recesses between the plastic foil and thesheet. Preferably the strength of the sheet is such that the tablets orcapsules can be removed from the blister pack by manually applyingpressure on the recesses whereby an opening is formed in the sheet atthe place of the recess. The tablet or capsule can then be removed viasaid opening.

It may be desirable to provide a memory aid on the kit, e.g., in theform of numbers next to the tablets or capsules whereby the numberscorrespond with the days of the regimen which the tablets or capsules sospecified should be ingested. Another example of such a memory aid is acalendar printed on the card, e.g., as follows “First Week, Monday,Tuesday, . . . etc. . . . Second Week, Monday, Tuesday, . . . ” etc.Other variations of memory aids will be readily apparent. A “daily dose”can be a single tablet or capsule or several pills or capsules to betaken on a given day. Also, a daily dose of a compound of the presentinvention can consist of one tablet or capsule, while a daily dose ofthe second compound can consist of several tablets or capsules and viceversa. The memory aid should reflect this and aid in correctadministration of the active agents.

In another specific embodiment of the invention, a dispenser designed todispense the daily doses one at a time in the order of their intendeduse is provided. Preferably, the dispenser is equipped with amemory-aid, so as to further facilitate compliance with the regimen. Anexample of such a memory-aid is a mechanical counter which indicates thenumber of daily doses that has been dispensed. Another example of such amemory-aid is a battery-powered micro-chip memory coupled with a liquidcrystal readout, or audible reminder signal which, for example, readsout the date that the last daily dose has been taken and/or reminds onewhen the next dose is to be taken.

The compounds of the present invention and other pharmaceutically activecompounds, if desired, can be administered to a patient either orally,rectally, parenterally, (for example, intravenously, intramuscularly, orsubcutaneously) intracisternally, intravaginally, intraperitoneally,intravesically, locally (for example, powders, ointments or drops), oras a buccal or nasal spray. All methods that are used by those skilledin the art to administer a pharmaceutically active agent arecontemplated.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions, or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents,solvents, or vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving,wetting, emulsifying, and dispersing agents. Microorganism contaminationcan be prevented by adding various antibacterial and antifungal agents,for example, parabens, chlorobutanol, phenol, sorbic acid, and the like.It may also be desirable to include isotonic agents, for example,sugars, sodium chloride, and the like. Prolonged absorption ofinjectable pharmaceutical compositions can be brought about by the useof agents delaying absorption, for example, aluminum monostearate andgelatin.

Solid dosage forms for oral administration include capsules, tablets,powders, and granules. In such solid dosage forms, the active compoundis admixed with at least one inert customary excipient (or carrier) suchas sodium citrate or dicalcium phosphate or (a) fillers or extenders, asfor example, starches, lactose, sucrose, mannitol, and silicic acid; (b)binders, as for example, carboxymethylcellulose, alginates, gelatin,polyvinylpyrrolidone, sucrose, and acacia; (c) humectants, as forexample, glycerol; (d) disintegrating agents, as for example, agar-agar,calcium carbonate, potato or tapioca starch, alginic acid, certaincomplex silicates, and sodium carbonate; (a) solution retarders, as forexample, paraffin; (f) absorption accelerators, as for example,quaternary ammonium compounds; (g) wetting agents, as for example, cetylalcohol and glycerol monostearate; (h) adsorbents, as for example,kaolin and bentonite; and (i) lubricants, as for example, talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, or mixtures thereof. In the case of capsules, and tablets, thedosage forms may also comprise buffering agents.

Solid compositions of a similar type may also be used as fillers in softand hard filled gelatin capsules using such excipients as lactose ormilk sugar, as well as high molecular weight polyethylene glycols, andthe like.

Solid dosage forms such as tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells, such as entericcoatings and others well known in the art. They may also containopacifying agents, and can also be of such composition that they releasethe active compound or compounds in a certain part of the intestinaltract in a delayed manner. Examples of embedding compositions that canbe used are polymeric substances and waxes. The active compounds canalso be in micro-encapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Inaddition to the active compounds, the liquid dosage form may containinert diluents commonly used in the art, such as water or othersolvents, solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethylformamide, oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil, and sesame seed oil, glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, or mixtures of these substances, and the like.

Besides such inert diluents, the composition can also include adjuvants,such as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents. Suspensions, in addition to the activecompound, may contain suspending agents, as for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, and tragacanth, or mixtures of these substances, and thelike.

Compositions for rectal administration are preferable suppositories,which can be prepared by mixing the compounds of the present inventionwith suitable non-irritating excipients or carriers such as cocoabutter, polyethylene glycol or a suppository wax, which are solid atordinary room temperature, but liquid at body temperature, andtherefore, melt in the rectum or vaginal cavity and release the activecomponent.

Dosage forms for topical administration of a compound of the presentinvention include ointments, powders, sprays and inhalants. The activecompound or fit compounds are admixed under sterile condition with aphysiologically acceptable carrier, and any preservatives, buffers, orpropellants that may be required. Opthalmic formulations, eye ointments,powders, and solutions are also contemplated as being within the scopeof this invention.

The compounds of the present invention can be administered to a patientat dosage levels in the range of about 0.1 to about 3,000 mg per day.For a normal adult human having a body weight of about 70 kg, a dosagein the range of about 0.01 to about 100 mg per kilogram body weight istypically sufficient. The specific dosage and dosage range that can beused depends on a number of factors, including the requirements of thepatient, the severity of the condition or disease being treated, and thepharmacological activity of the compound being administered. Thedetermination of dosage ranges and optimal dosages for a particularpatient is within the ordinary skill in the art.

The compounds of the present invention can be administered aspharmaceutically acceptable salts, esters, amides or prodrugs. The term“salts” refers to inorganic and organic salts of compounds of thepresent invention. The salts can be prepared in situ during the finalisolation and purification of a compound, or by separately reacting apurified compound in its free base or acid form with a suitable organicor inorganic base or acid and isolating the salt thus formed.Representative salts include the hydrobromide, hydrochloride, sulfate,bisulfate, nitrate, acetate, oxalate, palmitiate, stearate, laurate,borate, benzoate, lactate, phosphate, tosylate, citrate, maleate,fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate,lactobionate, and laurylsulphonate salts, and the like. The salts mayinclude cations based on the alkali and alkaline earth metals, such assodium, lithium, potassium, calcium, magnesium, and the like, as well asnon-toxic ammonium, quaternary ammonium, and amine cations including,but not limited to, ammonium, tetramethylammonium, tetraethylammonium,methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine,and the like. See, for example, S. M. Berge, et al., “PharmaceuticalSalts,” J Pharm Sci, 66: 1-19 (1977).

Examples of pharmaceutically acceptable esters of the compounds of thepresent invention include C₁-C₈ alkyl esters. Acceptable esters alsoinclude C₅-C₇ cycloalkyl esters, as well as arylalkyl esters such asbenzyl. C₁-C₄ alkyl esters are commonly used. Esters of compounds of thepresent invention may be prepared according to methods that are wellknown in the art.

Examples of pharmaceutically acceptable amides of the compounds of thepresent invention include amides derived from ammonia, primary C₁-C₈alkyl amines, and secondary C₁-C₈ dialkyl amines. In the case ofsecondary amines, the amine may also be in the form of a 5 or 6 memberedheterocycloalkyl group containing at least one nitrogen atom. Amidesderived from ammonia, C₁-C₃ primary alkyl amines and C₁-C₂ dialkylsecondary amines are commonly used. Amides of the compounds of thepresent invention may be prepared according to methods well known tothose skilled in the art.

The term “prodrug” means compounds that are transformed in vivo to yielda compound of the present invention. The transformation may occur byvarious mechanisms, such as through hydrolysis in blood. A discussion ofthe use of prodrugs is provided by T. Higuchi and W. Stella, “Prodrugsas Novel Delivery Systems,” Vol. 14 of the A.C.S. Symposium Series, andin Bioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

To illustrate, if the compound of the invention contains a carboxylicacid functional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as(C₁-C₈ alkyl, (C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl havingfrom 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl having from 5 to10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbonatoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)aminomethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as (3-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂₋₃)alkyl.

Similarly, if a compound of the present invention comprises an alcoholfunctional group, a prodrug can be formed by the replacement of thehydrogen atom of the alcohol group with a group such as(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanoyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, —P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate).

The compounds of the present invention may contain asymmetric or chiralcenters, and therefore, exist in different stereoisomeric forms. It iscontemplated that all stereoisomeric forms of the compounds as well asmixtures thereof, including racemic mixtures, form part of the presentinvention. In addition, the present invention contemplates all geometricand positional isomers. For example, if the compound contains a doublebond, both the cis and trans forms (designated as S and E,respectively), as well as mixtures, are contemplated.

Mixture of stereoisomers, such as diastereomeric mixtures, can beseparated into their individual stereochemical components on the basisof their physical chemical differences by known methods such aschromatography and/or fractional crystallization. Enantiomers can canalso be separated by converting the enantiomeric mixture into adiastereomeric mixture by reaction with an appropriate optically activecompound (e.g., an alcohol), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereomers to the correspondingpure enantiomers. Also, some compounds may be atropisomers (e.g.,substituted biaryls).

The compounds of the present invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater (hydrate), ethanol, and the like. The present inventioncontemplates and encompasses both the solvated and unsolvated forms.

It is also possible that compounds of the present invention may exist indifferent tautomeric forms. All tautomers of compounds of the presentinvention are contemplated. For example, all of the tautomeric forms ofthe tetrazole moiety are included in this invention. Also, for example,all keto-enol or imine-enamine forms of the compounds are included inthis invention.

Those skilled in the art will recognize that the compound names andstructures contained herein may be based on a particular tautomer of acompound. While the name or structure for only a particular tautomer maybe used, it is intended that all tautomers are encompassed by thepresent invention, unless stated otherwise.

It is also intended that the present invention encompass compounds thatare synthesized in vitro using laboratory techniques, such as those wellknown to synthetic chemists; or synthesized using in vivo techniques,such as through metabolism, fermentation, digestion, and the like. It isalso contemplated that the compounds of the present invention may besynthesized using a combination of in vitro and in vivo techniques.

The present invention also includes isotopically-labelled compounds,which are identical to those recited herein, but for the fact that oneor more atoms are replaced by an atom having an atomic mass or massnumber different from the atomic mass or mass number usually found innature. Examples of isotopes that can be incorporated into compounds ofthe invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl. In one aspect, the present inventionrelates to compounds wherein one or more hydrogen atom is replaced withdeuterium (²H) atoms.

Compounds of the present invention that contain the aforementionedisotopes and/or other isotopes of other atoms are within the scope ofthis invention. Certain isotopically-labelled compounds of the presentinvention, for example those into which radioactive isotopes such as ³Hand ¹⁴C are incorporated, are useful in drug and/or substrate tissuedistribution assays. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C,isotopes are particularly preferred for their ease of preparation anddetection. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased in vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of this inventioncan generally be prepared by substituting a readily availableisotopically labelled reagent for a non-isotopically labelled reagent.

The compounds of the present invention may exist in various solid statesincluding crystalline states and as an amorphous state. The differentcrystalline states, also called polymorphs, and the amorphous states ofthe present compounds are contemplated as part of this invention.

In synthesizing compounds of the present invention, it may be desirableto use certain leaving groups. The term “leaving groups” (“LG”)generally refer to groups that are displaceable by a nucleophile. Suchleaving groups are known in the art. Examples of leaving groups include,but are not limited to, halides (e.g., I, Br, F, Cl), sulfonates (e.g.,mesylate, tosylate), sulfides (e.g., SCH₃), N-hydroxsuccinimide,N-hydroxybenzotriazole, and the like. Examples of nucleophiles include,but are not limited to, amines, thiols, alcohols, Grignard reagents,anionic species (e.g., alkoxides, amides, carbanions) and the like.

All patents, published patent applications and other publicationsrecited herein are hereby incorporated by reference.

The examples presented below illustrate specific embodiments of thepresent invention. These examples are meant to be representative and arenot intended to limit the scope of the claims in any manner. Unlessotherwise noted, when a percent is used herein with respect to a solid,the percent is by weight with respect to the referenced solidcomposition. When a percent is used herein with respect to a liquid, thepercent is by volume with respect to the referenced solution.

¹H-NMR spectra were typically acquired on a Bruker Avance III 500spectrometer system (Bruker, Bilerica, Mass.) operating at a ¹Hfrequency of 500.13 MHz, equipped with a Bruker 5 mm PABBI probe with az-axis gradient; or on a Bruker Avance II 400 spectrometer operating ata ¹H frequency of 400.23 MHz, equipped with a Bruker 5 mm PABBO probewith a z-axis gradient. Samples were typically dissolved in 500 μL ofeither DMSO-d₆ or CD₃OD for NMR analysis. ¹H chemical shifts arereferenced to the residual solvent signals from DMSO-d₆ at δ 2.50 andCD₃OD at δ 3.30.

Significant peaks are tabulated and typically include: number ofprotons, multiplicity (s, singlet; d, doublet; dd, doublet of doublets;t, triplet; q, quartet; m, multiplet; br s, broad singlet) and couplingconstant(s) in Hertz.

Electron Ionization (EI) mass spectra were typically recorded on anAgilent Technologies 6140 Quadrupole LC/MS mass spectrometer. Massspectrometry results are reported as the ratio of mass over charge,sometimes followed by the relative abundance of each ion (inparentheses). Starting materials in the Examples below are typicallyeither available from commercial sources such as Sigma-Aldrich, St.Louis, Mo., or via literature procedures.

The following abbreviations may be used herein:

~ about +ve or pos. ion positive ion Δ heat Ac acetyl Ac₂O aceticanhydride aq aqueous AcOH acetic acid Bn benzyl Boctert-butyloxycarbonyl BSA bovine serum albumin Bu butyl Bz benzoyl Calcdor Calc'd calculated Conc. concentrated CSA camphor-10-sulfonic acid dday(s) DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE dichloroethane DCMdichloromethane DEA diethylamine Dess-Martin1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol- periodinane; 3-(1H)-oneDess-Martin reagent DIEA or DIPEA diisopropylethylamine DMAP4-dimethylaminopyridine DME 1,2-dimethoxyethane DMFN,N-dimethylformamide DMSO dimethyl sulfoxide dr diastereomeric ratioDTT dithiothreitol DVB divinylbenzene EDCN-Ethyl-N′-(3-dimethylaminopropyl)carbodiimide eq equivalent ESI or ESelectrospray ionization Et ethyl Et₂O diethyl ether Et₃N triethylamineEtOAc ethyl acetate EtOH ethyl alcohol g gram(s) h hour(s) HATUO-(7-azabenzotriazol-1-yl)-N,N,N′,N′- tetramethyluroniumhexafluorophosphate HBTU O-benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluorophosphate Hex hexanes HMPA hexamethylphosphoramide HOAt1-hydroxy-7-azabenzotriazole HOBt hydroxybenzotriazole HPLC highpressure liquid chromatography IPA or iPrOH isopropyl alcohol Jonesreagent solution of chromium(IV)oxide and sulfuric acid in water KHMDSpotassium hexamethyldisilazide KOAc potassium acetate LCMS, LC-MS orliquid chromatography mass spectrometry LC/MS LDA lithiumdiisopropylamide LHMDS or LiHMDS lithium hexamethyldisilazideL-Selectride ® lithium tri-sec-butylborohydride (Sigma-Aldrich, St.Louis) M molar (mol L⁻¹) m/z mass divided by charge mCPBAm-chloroperoxybenzoic acid Me methyl MeCN acetonitrile MeI iodomethaneMeOH methyl alcohol mg milligram(s) min minute(s) mL milliliter(s) Mmole(s) MS mass spectrometry MsCl methanesulfonyl chloride MTBE or MtBEmethyl tert-butyl ether m/z mass-to-charge ratio NaHMDS sodiumhexamethyldisilazide NaOtBu sodium tert-butoxide NBS N-bromosuccinimidenBuLi n-butyl lithium NMO N-methylmorpholine-N-oxide NMP1-methyl-2-pyrrolidinone NMR nuclear magnetic resonance N-Selectride ®sodium tri-sec-butylborohydride (Sigma-Aldrich, St. Louis) PBS phosphatebuffered saline PMB paramethoxybenzyl Pr propyl ppm parts per millionrac racemic RP-HPLC or reversed phase high pressure liquid RPHPLCchromatography RT or rt room temperature sat. or sat'd or satd saturatedSFC supercritical fluid chromatography TBAF tetrabutylammonium fluorideTBDMS tert-butyldimethylsilyl TBDMS-Cl tert-butyldimethylsilyl chlorideTBDPS tert-butyldiphenylsilyl TEMPO(2,2,6,6-tetramethylpiperidin-1-yl)oxidanyl tert or t tertiary TFAtriflouroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TLC thinlayer chromatography TMS trimethylsilyl or trimethylsilane TPAPtetrapropylammonium perruthenate t_(R) retention time tBuOH tert-butylalcohol v/v volume per volume

EXAMPLES General Synthetic Schemes

Compounds of the present invention generally can be prepared beginningwith commercially available starting materials and using synthetictechniques known to those of skill in the art. Outlined below are somereaction schemes suitable for preparing compounds of the presentinvention. Further exemplification is found in the specific examplesprovided.

As shown in Scheme 1, compounds of the present invention wherein R^(a)and R^(b) are both H, can be prepared by reacting a suitably substitutedaryl acetic acid 1 and an aryl carboxylic acid 2 in an organic solventor mixture of solvents (including aqueous mixtures) in the presence of abase, such as LHMDs or KHMDS to provide, after workup, a compound offormula 3. Treatment of 3 with methyl acrylate in the presence of abase, such as tBuOK results in the formation of a 4,5-substituted5-oxopentanoate, which can be reduced with a reducing reagent such asNaBH₄ or LiBEt₃H in a suitable solvent such as THF, diethylether ordimethoxyethane to produce racemic compound 4. 5 can in turn be obtainedfrom 4 by converting the alcohol into a toluenesulfonate,methanesulfonate, or trifluoromethanesulfonate, followed by reactionwith sodium azide in a suitable solvent such as, for example, DMF, DMEor acetone. The azide can be reduced to a primary amine by a number ofreducing agents including NaBH₄, H₂ and a catalyst, triphenylphosphineand trimethylphoshine, which in turn, upon treatment with a base, suchas LiOH, K₂CO₃ or NaHCO₃ in an aqueous mixture with a suitable organicsolvent, such as THF will cyclize to the piperidin-2-one 6. Individualenantiomers of racemic 6 can be separated by chiral HPLC using, forexample, a Chiralcel® OD-H 20 mm I.D.×250 mm column (Daicel ChemicalIndustries LTD, Fort Lee, N.J.) using 40% isopropyl alcohol/hexane asthe eluent.

As shown in Scheme 2, the piperidin-2-one 6 can be further modified, forexample by arylating or alkylating the nitrogen by methods well known tothose of ordinary skill in the art. For example, reacting 6 with analkyl halide in the presence of a base such as sodium hydride in asolvent such as DME, DMF or THF will accomplish this transformation. 7may be further alkylated by treatment with a base such as lithiumdiisopropylamide or lithium hexamethyldisilazide in a suitable solventsuch as THF, followed by reaction with an alkylating agent, such as analkyl halide, alkyl methanesulfonate, alkyl trifluoromethanesulfonate,or alkyl toluenesulfonate to give intermediate 8. If desired, thesequence may be repeated to give compounds of the general formula 9. LGis a leaving group.

As shown in Scheme 3, the group attached to the nitrogen can potentiallybe removed to give intermediate 16. For example treating a2,4-dimethoxybenzyl derivative with TFA accomplishes such atransformation. Similar transformations are well documented (see e.g. P.G. M. Wuts and T. W. Greene, “Greene's protective groups in organicsynthesis”, 4^(th) ed., John Wiley & Sons, New York, (2007)).Resubjecting compound 16 to alkylation conditions similar to the onesdescribed above will give 17.

As further shown in Scheme 3, if one of the alkyl groups contains adouble bond, this double bond can be converted into a carboxylic acid 11by a number of methods known to those of ordinary skill in the art. Forexample, reacting 10 with a solution of periodate containing KMnO₄ orRuCl₃ (see e.g. R. U. Lemieux, E. von Rudloff, Can. J. Chem., 38, 1703,(1955)) will accomplish this transformation. The carboxylic acid 11 can,in turn, be converted into other groups such as an amide or hydrazide bymethods well known to those of ordinary skill in the art. For example,the carboxylic acid 11 can be activated by condensation with a varietyof coupling reagents, including hydroxybenzotriazole (HOBt) andN-hydroxysuccinimide (HOSu), for example, using dicyclohexylcarbodiimide(DCC) or a similar carbodiimide reagent or a wide variety of reagentssuch as those developed for formation of peptide bonds. Conditions forsuch reactions are well known to those of ordinary skill in the art. Theactivated intermediate, an ester of HOBt or HOSu, for example, can thenbe condensed with a wide variety of nucleophiles such as amines oralcohols.

Scheme 3 shows the conversion of a compound of formula II into an amide12 by this sequence. Using ammonia as the nucleophile, compound 13 isobtained. Dehydration of the amide 13 to a nitrile 14 can beaccomplished by a variety of methods. Phosphorous pentoxide is a commondehydrating reagent for this reaction, but many others are known tothose skilled in the art (see e.g. R. C. Larock; Comprehensive OrganicTransformations, 2^(nd) ed., John Wiley & Sons, New York, pp. 1983,(1999)). The nitrile can, in turn, be converted into other groups suchas a tetrazole by reacting the nitrile with an azide, such as sodiumazide, lithium azide or hydrazoic acid in a solvent such as DMF orwater.

As shown in Scheme 4, the acid 11 can also be used to produceheterocyclic derivatives, such as, for example, [1,3,4]-oxadiazoles 18,[1,2,4]-oxadiazol-5(4H)-ones 19, and [1,2,4]-oxadiazoles 20 by methodswell known to those of ordinary skill in the art. For example,converting the acid 11 into an diacylhydrazide, followed by treatmentwith a base at elevated temperature will provide 18. In another example11 is converted into a nitrile as described in Scheme 3, which istreated with hydroxylamine. Reaction with 1,1′-carbonyldiimidazole inthe presence of a base, such as DBU, generates 19 In yet anotherexample, 11 reacts with a N-hydroxycarboxamidine derivative in thepresence of 1,1′-carbonyldiimidazole, followed by treatment withtetrabutylammonium fluoride to give 20.

As shown in Scheme 5, a compound of formula 16 can also bedihydroxylated to give 21. Osmiumtetroxide in the presence of a secondoxidizing agent such as 4-methylmorpholine-4-oxide in a suitable solventwill accomplish such a transformation. 21 can be converted into 22 byreaction with acetone or 2,2-dimethoxypropane in the presence of anacid, such as methanesulfonic acid, p-toluenesulfonic caid orcamphorsulfonic acid. Compound 22 can then be N-arylated or N-alkylatedby a variety of methods well known to those of ordinary skill in theart, such as treating 22 with an alkylhalide, alkylmethanesulfonate oralkyltoluenesulfonate in the presence of a base such as butyllithium orsodium hydride in a solvent such as DME, DMF or THF. Treating 23 with anacid such as HCl or H₂SO₄ in the presence of water will give the diol24, which can be cleaved to the aldehyde 25 by a variety of oxidizingagents, such as periodic acid or lead tetraacetate (see e.g. Haines, A.H. Methods for the Oxidation of Organic Compounds, Vol 2; p 277,Academic Press, NY, (1988)). The aldehyde 25 can be converted into theacid 26 by strong oxidizing agents including CrO₃ or a solution ofperiodate containing RuCl₃.

Scheme 6 illustrates an alternative method for the preparation ofintermediate compounds of general structure 35. This intermiate can beused to make additional compounds in this invention. Here, a(4S,5S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-1,3,2-oxazasilolidine ofthe general formula 28 is formed by the reaction of 27 (prepared asdescribed in J. Am. Chem. Soc. 124, 7920, (2002) with an alkene in thepresence of Grubb's catalyst. Reaction with imine 29, which is preparedby the reaction of 2-(aminomethyl)phenol with an aldehyde usingconditions well known to those skilled in the art, will yield compound30 (See also J. Am. Chem. Soc. 129, 14552, (2007)). Intermediate 30 canin turn be converted into compound 31, by reacting consecutively withacetic anhydride in the presence of a base such as triethylamine,toluenesulfonic acid and oxalyl chloride in the presence of propyleneglycol as described in Org. Letters, 11, 433, (2009), for example.Homoallyl amine 31 can optionally be further modified, for example byarylating or alkylating the nitrogen by methods well known to those ofordinary skill in the art. For example, the reaction of 31 with a ketoneor aldehyde in the presence of a reducing agent such as sodiumborohydride, sodium cyanoborohydride or sodium triacetoxyborohydride ina solvent such as DME, DMF or THF will accomplish this transformation.32 can be acylated or sulfonylated by conditions well known to those ofordinary skill in the art to yield 33. 33 can be cyclized to 34 by aRing Closing Metathesis (RCM) reaction. Catalysts suitable for suchtransformations are known to those of skill in the art (see e.g. (a)Grubbs, R. H. Handbook of Metathesis; Wiley-VCH: Weinheim, (2003); (b)Angew. Chem., Int. Ed., 42, 1900, (2003)) and include Grubbs 1^(st)generation and Grubbs 2^(nd) generation catalysts. Catalytichydrogenation of 34 using, for example, a palladium, platinum or iridiumcatalyst in a solvent such as DCM, THF, methanol, or an aqueous mixturecontaining an alcohol or THF as a co-solvent, for example, is used toreduce the double bond, producing compound 35.

Compounds of the present invention may also be prepared via the lactoneroute illustrated in Scheme 7. Aryl benzyl ketones 3, commerciallyavailable or prepared by Dieckmann condensation or by coupling an arylmethyl ketone 41 with a bromoaryl compound 42, can be condensed withacrylate esters 43 including methacrylate, ethacrylate, etc., to formthe keto ester 44. Stereoselective reduction occurs with sodiumborohydride in methanol to form racemic 45 as a mixture of epimers atthe R^(e) position. Alternatively, this reduction can be carried out viadynamic kinetic resolution (see, Chen, et. al., Organic Process Research& Development, 2007, 11, 616-623 and references contained therein) togive enantioenriched 46, also as a mixture of epimers at the R″position. In this process, isopropyl esters are produced bytransesterification. Hydrolysis to the carboxylic acid 47 followed bylactonization affords the racemic or enantioenriched lactone 48 as amixture of diastereomers at the R^(e) position. The diastereomers as amixture can be enolized with strong base such as LiHMDS or LDA to give acommon enolate which is alkylated with allyl bromide to afford lactone49 as a single diastereomer. (see Example 261 Step E). Condensation ofracemic lactone 49 with enantiopure aminoalcohols 50 results indiastereomeric hydroxylamides 51 which can be converted into oxazolines52, oxazolinium salts 53 or hydroxylactams 54. Separation of thediastereomers can generally be done on any of these intermediates bynormal phase silica chromatography. Alternatively, condensation ofenantioenriched lactone 49 with enantioenriched amino alcohols 50 leadsto enhanced enantiopurity of the resulting 51, 52, 53 or 54. For example94% ee lactone combined with 98% ee amino alcohol results in the majordiastereomer of 99.94% ee.

Hydroxylactam 54 (R⁵=Et, cPr) has been prepared by alternate procedures(see Example 91 Step B; and Example 252 Step A) and used as anintermediate for many of the compounds of the present invention(equivalent to lactam 10 of Scheme 3). Using the lactone procedure,additional examples (R⁵=iPr [Example 261, Step H], tBu, etc.) can beprepared. Additionally, aminoalcohols containing two adjacentstereocenters (i.e., R⁶ not H) can be incorporated into this route. Theoxazolinium salt 53 is also a versatile intermediate. It can beintercepted with various nucleophiles such as azide, thiols or sulfinatesalts to form lactams 56, leading to amines, amides, sulfonamides andsulfones. The allyl group of oxazolinium salt 53 can be oxidized to thecarboxylic acid oxidation state with minimal complication from theprimary or secondary alcohol center which is tied up in the oxazolinering. The resulting orthoamide 57 releases the lactam carboxylate 58under mild hydrolysis conditions. Thus lactone 49 [R³=pClPh, R⁴=mClPh,R=Me] and (2S,3S)-3-aminopentan-2-ol [WO2007/110649A2] were combined.The corresponding oxazoline 52 [R³=pClPh, R⁴=mClPh, R^(e)=Me R⁵=Et,R=Me] was formed by dehydration under Dean-Stark conditions in toluenewith ammonium molybdate as a catalyst. Treatment with triflic anhydridein dichloromethane with lutidine at −50° C. gave oxazolinium salt 53[R³=pClPh, R⁴=mClPh, R^(e)=Me R⁵=Et, R⁶=Me]. Oxidation with KMnO₄ indichloromethane/water facilitated by tetrabutylammonium chloride gaveafter workup and hydrolysis with sodium bicarbonate solution inisopropyl acetate at 70° C., compound 58 [R³=pClPh, R⁴=mClPh, R^(e)=MeR⁵=Et, R⁶=Me] identical to material prepared in Example 152.

Example 1

2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid Step A. 2-(3-Chlorophenyl)-1-(4-chlorophenyl)ethanone

To a solution of 2-(3-chlorophenyl)acetic acid (10 g, 58.6 mmol) in THF(58 ml) was added 117 mL of a 1M solution of sodiumbis-(trimethylsilyl)amide in THF slowly over 1 h at −78° C. After beingstirred at −78° C. for 40 min, a solution of methyl 4-chlorobenzoate (10g, 58.6 mmol) in THF (35 ml) was added over a period of 10 min. Thereaction was stirred at −78° C. for 3 h, then allowed to warm to 25° C.,and stirred an additional 2 h until completion. The reaction wasquenched with saturated aqueous NH₄Cl solution and most of the THF wasremoved under reduced pressure. The residue was extracted with ethylacetate (2×100 ml). The combined organic layers were washed with sat.NaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The product was recrystallized from ether/pentane toprovide the title compound as a white solid.

Step B. Methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-oxopentanoate

To a solution of 52.1 g (197 mmol) of2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (Example 1, Step A) andmethyl acrylate (19.5 ml, 216 mmol) in 360 mL of THF was added 20 mL ofa 1M solution of potassium tert-butoxide in THF slowly at 0° C. over aperiod of 20 min (reaction solution temp kept<10° C.). The reaction wasallowed to warm to ambient temperature. After being stirred at rt for 1h, the reaction was concentrated under reduced pressure, diluted withwater and extracted with ethyl acetate. The combined organic layers werewashed with sat. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by flashchromatography on silica gel (eluent: 15% EtOAc/hexanes) provided thetitle compound as a colorless liquid. R is CH₃.

Step C. (4S,5S)-Methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxypentanoate and (4R,5R)-Methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy pentanoate

To a solution of 75.1 g (213 mmol) of methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-oxopentanoate (Example 1, StepB) in MeOH (0.71 L, c=0.3 M) at 0° C. was added sodium borohydride (8058mg, 213 mmol) in several small portions. After being stirred at 0° C.for 30 min, the reaction mixture was quenched with ice-cold H₂O,concentrated under reduced pressure, and extracted with EtOAc. Thecombined organic layers were washed (sat. aq. NaCl solution), dried overNa₂SO₄, filtered and the filtrate was concentrated. Purification of theresidue by flash chromatography on silica gel (eluent: 20 to 30%EtOAc/hexanes, gradient elution) provided a racemic mixture of the titlecompounds as a colorless liquid.

Step D. (4S,5R)-Methyl5-azido-4-(3-chlorophenyl)-5-(4-chlorophenyl)pentanoate and(4R,5S)-Methyl 5-azido-4-(3-chlorophenyl)-5-(4-chlorophenyl)pentanoate

To a solution of 63.1 g (179 mmol) of (4S,5S)-methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy pentanoate and(4R,5R)-methyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxypentanoate (Example 1, Step C) and triethylamine (49.8 ml, 357 mmol) inDCM (600 mL, 0.3 M) was added methanesulfonyl chloride (18 ml, 232 mmol)at 0° C. dropwise over a period of 10 min. The reaction was stirred at0° C. for 40 min and monitored by TLC for completion. Then the reactionwas quenched with ice-cold water, extracted (3×DCM), and washed with sataq. NaCl solution. The combined organic layers were dried (Na₂SO₄), andconcentrated under the reduced pressure.

The crude mesylate synthesized above was dissolved in DMF (350 mL, 0.5M) and sodium azide (58 g, 893 mmol) was added in several portions. Themixture was heated to 100° C. and after being stirred at 100° C. for 30min, the reaction mixture was cooled to room temperature, diluted withwater and extracted with EtOAc. The combined organic layers were washed(sat. aq. NaCl solution), dried over Na₂SO₄, filtered and the filtratewas concentrated. Purification of the residue by flash chromatography onsilica gel (eluent: 5 to 20% EtOAc/hexanes, gradient elution) providedthe title compound as a colorless liquid.

Step E. (5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one

To a solution of 45.9 g (121 mmol) of methyl5-azido-4-(3-chlorophenyl)-5-(4-chlorophenyl) pentanoate (Example 1,Step D) in THF/H₂O (4:1, 375 mL) was added 152 mL of a 1M solution oftrimethylphosphine in THF (152 mmol). After being stirred for 1 h at 25°C., most of the THF was removed under reduced pressure. The residue wasbasified (ice-cold 2 M LiOH) and the product was extracted withmethylene chloride. The combined organic layers were washed with sat.NaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure to provide a white solid.

This solid was dissolved in MeOH/saturated aq. NaHCO₃ (4:1, 2.4 L,c=0.05 M) and the reaction was heated to reflux for 3 h. Excess organicsolvent was removed under reduced pressure, the residue was diluted withwater and extracted (2×10% MeOH/DCM). The combined organic layers werewashed with sat. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure to providetrans-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one as a mixtureof stereoisomers. Individual stereoisomers were separated by chiral HPLC(flowrate: 18 ml/min on a Chiralcel® OD-H 20 mm I.D.×250 mm, 5 miccolumn (Daicel Inc., Fort Lee, N.J.), using 40% isopropyl alcohol/hexaneas the eluent) to to give the title compound (t_(R)=8.2 min) as a whitesolid.

[α]_(D)=+158 (T=23.4° C., c=1.12, MeOH); ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 7.21 (2 H, d, J=8.2 Hz), 7.09-7.19 (3 H, m), 7.04-7.01 (1 H, m),6.97 (2 H, d, J=8.2 Hz), 6.80-6.77 (1 H, m), 5.83 (1 H, s, br), 4.51 (1H, d, J=9.8 Hz), 2.94-2.77 (1 H, m), 2.74-2.60 (2 H, m), 2.34-2.20 (1 H,m), 2.17-2.08 (1 H, m); MS (ESI) 320.0 [M+H]⁺.

Also obtained by the above method was the enantiomer of the titlecompound, (5S,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one:t_(R)=12.4 min; [α]_(D)=−156 (T=23.4° C., c=1.13, MeOH).

Step F. tert-butyl(2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoateand tert-butyl(2R)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoate

To a solution of 13.5 g (42.2 mmol) of(5R,6S)-5,6-bis(4-chlorophenyl)piperidin-2-one (Example 1, Step E) in140 mL of DMF was added 4.22 g (105 mmol) of a dispersion of 60% sodiumhydride in mineral oil at 0° C. After being stirred for 20 min,tert-butyl 2-bromobutanoate (28.2 g, 126 mmol) was added at 0° C. andthe resulting solution was stirred at 25° C. for 1.5 h until completionof the reaction. Then sat. aq. NH₄Cl solution was added and the mixturewas extracted with ethylacetate. The combined organic layers were washedwith water and sat. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification of theresidue by flash chromatography on silica gel (eluent: 20 to 50%EtOAc/hexanes, gradient elution) provided tert-butyl(2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoateas the faster eluting minor isomer:

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (2 H, d, J=8.2 Hz), 7.20-7.10(2 H, m), 7.08 (2 H, t, J=8.2 Hz) 6.99-6.96 (1 H, m), 6.77-6.73 (1 H,m), 4.48 (1 H, d, J=9.4 Hz), 3.24 (1 H, t, J=7.0 Hz), 3.04-2.94 (1 H,m), 2.72-2.58 (2 H, m), 2.25-2.00 (3 H, m), 1.93-1.82 (1 H, m), 1.45 (9H, s), 0.98 (3 H, t, J=7.4 Hz); MS (ESI) 462.1 [M+H]⁺.

Further elution provided tert-butyl(2R)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoateas the slower eluting major isomer

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J=8.2 Hz), 7.18-7.10(2 H, m), 7.01 (2 H, d, J=8.2 Hz), 7.02-6.98 (1 H, m), 6.82-6.78 (1 H,m), 5.83 (1 H, s), 4.54 (1 H, d, J=9.8 Hz), 3.09 (1 H, dd, J=8.2, 4.3Hz), 3.05-2.99 (1 H, m), 2.70-2.64 (2 H, m), 2.28-2.18 (2 H, m),2.08-2.02 (1 H, m), 1.48 (9 H, s), 0.57 (3 H, t, J=7.4 Hz); MS (ESI)462.1 [M+H]⁺.

Step G. tert-Butyl(2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoateand tert-Butyl(2S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate

To a solution of 1.45 g (3.14 mmol) of tert-butyl(2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxo-1-piperidinyl)butanoate(Example 1, Step F) and allyl bromide (0.326 mL, 3.76 mmol) in 12.5 mLof THF was added dropwise at −78° C. 3.3 mL of a 1 M solution of lithiumbis(trimethylsilyl)-amide in THF (3.3 mmol). After being stirred at −78°C. for 3 h, the reaction was quenched with sat. aqueous NH₄Cl solution,extracted with ethyl acetate. The combined organic layers were washedwith sat. NaCl solution, dried over Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure. Purification of the residue byflash chromatography on silica gel (50 g SiO₂, eluent: 5 to 20%EtOAc/hexanes, gradient elution) provided tert-butyl(2S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoateas the faster eluting major isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27-7.24 (2 H, m), 7.21-7.12 (2 H,m), 7.11-7.00 (3 H, m), 6.93-6.87 (1 H, m), 5.90-5.77 (1 H, m),5.19-5.09 (2 H, m), 4.64 (1 H, d, J=8.6 Hz), 3.21-3.10 (2 H, m),2.80-2.71 (1 H, m), 2.70-2.63 (1 H, m), 2.56-2.48 (1 H, m), 2.30-2.15 (2H, m), 2.07-1.99 (1 H, m), 1.60-1.48 (1 H, m), 1.47 (9 H, s), 0.61 (3 H,t, J=7.6 Hz); MS (ESI) 446.0 [M+H]⁺.

Further elution provided tert-butyl(2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoateas the slower eluting, minor isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J=8.2 Hz), 7.19-7.07(2 H, m), 7.01-6.95 (3 H, m), 6.77-6.72 (1 H, m), 5.95-5.77 (1 H, m),5.16-4.99 (2 H, m), 4.51 (1 H, d, J=10.6 Hz), 3.13-3.04 (1 H, m), 2.94(1 H, dd, J=7.8, 4.3 Hz), 2.87-2.77 (1 H, m), 2.68-2.58 (1 H, m),2.39-2.27 (2 H, m), 2.16-1.95 (2 H, m), 1.54-1.50 (1 H, m), 1.51 (9 H,s), 0.55 (3 H, t, J=7.4 Hz); MS (ESI) 446.0 [M+H]⁺.

Step H.2-((3R,5R,6S)-1-((S)-1-tert-Butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid

To a rapidly stirring solution of 842 mg (1.67 mmol) of tert-butyl(2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate(Example 1, Step G) in a mixture of 7 mL of water, 5 mL of acetonitrileand 5 mL of CCl₄ was added sodium periodate (1.43 g, 6.70 mmol),followed by ruthenium(III) chloride hydrate (37.8 mg, 0.168 mmol). Afterbeing stirred vigorously for 18 h, the reaction was acidified (10%citric acid) and diluted with EtOAc. The reaction mixture was filteredthrough celite and the filtrate was extracted with EtOAc. The combinedorganic layers were washed with sat. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Theresidue was purified by reversed phase preparatory HPLC (Gemini™ PrepC18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 80%acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) to give thetitle compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.35 (2 H, d, J=8.6 Hz), 7.27-7.24(3 H, m), 7.22-7.16 (1 H, m), 7.18 (2 H, d, J=8.6 Hz), 4.85 (1 H, d,J=5.1 Hz), 3.36 (1 H, dd, J=8.6, 3.5 Hz), 3.18-3.14 (1 H, m), 2.92-2.80(2 H, m), 2.79-2.72 (1 H, m), 2.32-2.18 (2 H, m), 2.15-2.06 (1 H, m),1.63-1.50 (1 H, m), 1.44 (9 H, s), 0.67 (3 H, t, J=7.4 Hz); MS (ESI)520.2 [M+H]⁺, 518.0 [M−H]⁻.

Example 2

2-((3S,5R,6S)-1-((S)-1-tert-Butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacidThe title compound was prepared from (S)-tert-butyl2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate(Example 1, Step G) by the procedure described in Example 1, Step H.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.27-7.26 (2 H, m), 7.12-7.16 (1 H,m), 7.13-7.10 (1 H, m), 7.02-6.94 (3 H, m), 6.74-6.71 (1 H, m), 4.51 (1H, d, J=10.8 Hz), 3.18-3.08 (2 H, m), 3.06-2.96 (2 H, m), 2.47 (1 H, dd,J=15.4, 3.2 Hz), 2.35-2.25 (1 H, m), 2.24-2.12 (2 H, m), 1.52-1.57 (1 H,m), 1.51 (9 H, s), 0.56 (3 H, t, J=7.5 Hz); MS (ESI) 520.2 [M+H]⁺, 518.0[M−H]⁻.

The following examples 3 to 6 were prepared as described in Example 1,substituting tert-butyl 2-bromobutanoate in step F, with the appropriateamount of ethyl 2-bromobutanoate, ethyl 2-bromo-3-methylpentanoate,ethyl 2-bromopentanoate, and ethyl 2-bromo-2-cyclopropylacetate,respectively.

Example 3

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42-7.33 (3 H, m), 7.32-7.28 (3 H,m), 7.27-7.24 (2 H, m), 4.91 (1 H, d, J=3.5 Hz), 4.23-4.10 (2 H, m),3.54 (1 H, dd, J=8.6, 3.5 Hz), 3.22-3.16 (1 H, m), 2.84-2.73 (3 H, m),2.38-2.30 (2 H, m), 2.05-1.97 (1 H, m), 1.60-1.50 (1 H, m), 1.27 (3 H,t, J=7.4 Hz), 0.70 (3 H, t, J=7.4 Hz); MS (ESI) 491.8 [M+H]⁺, 489.9[M−H]⁻.

Example 4

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-4-methyl-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.34 (d, J=6.7 Hz, 3 H), 0.77 (d,J=6.7 Hz, 3 H), 1.13 (m, 1 H), 1.28 (t, J=7.1 Hz, 3 H), 1.30-1.44 (m, 1H), 1.98 (m, 1 H), 2.32-2.47 (m, 2 H), 2.75 (m, 1 H), 2.79-2.86 (m, 2H), 3.14-3.19 (m, 1 H), 3.66 (dd, J=9.2, 2.4 Hz, 1 H), 4.11-4.24 (m, 2H), 4.95 (m, 1 H), 7.23-7.34 (m, 5 H), 7.36-7.41 (m, 3 H), MS (ESI)520.2 [M+H]⁺. 518.0 [M−H]⁻.

Example 5

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)aceticacid and2-((3S,5S,6R)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxopentan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The compounds described in Example 5 were derived from racemicpiperidinone which was prepared in Example 1, Step E.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40-7.37 (3 H, m), 7.31-7.27 (3 H,m), 7.27-7.24 (2 H, m), 4.92 (1 H, d, J=3.5 Hz), 4.20-4.10 (2 H, m),3.60 (1 H, dd, J=8.6, 3.5 Hz), 3.20-3.15 (1 H, m), 2.83-2.72 (3 H, m),2.40-2.30 (2 H, m), 2.03-1.97 (1 H, m), 1.44-1.37 (1 H, m), 1.27 (3 H,t, J=7.2 Hz), 1.26-1.17 (1 H, m), 0.92-0.80 (1 H, m), 0.54-0.78 (3 H, t,J=7.4 Hz); MS (ESI) 506.0 [M+H]⁺, 504.0 [M−H]⁻.

Example 6

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-ethoxy-2-oxoethyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.08 (1 H, m), 0.34 (1 H, m), 0.47(1 H, m), 0.58 (1 H, m), 1.06 (1 H, m), 1.13 (3 H, t, J=7.1 Hz), 1.83 (1H, m), 2.19 (1 H, m), 2.50-2.63 (2 H, m), 2.74 (1 H, dd, J=16, 6.8 Hz),3.08 (1 H, m), 3.42 (1 H, d, J=10.8 Hz), 3.97 (2 H, m), 5.20 (1 H, s),7.08 (1 H, m), 7.15-7.25 (7 H, m); MS (ESI) 504.1 [M+H]⁺.

Example 7

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of 300 mg (0.61 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid (Example 3) in 12 mL of Et₂O was added lithium tetrahydroborate(39.8 mg, 1.83 mmol) at 0° C. After being stirred for 20 min, methanol(37.0 μl, 914 μmol) was added at 0° C. and the resulting solution wasstirred at 25° C. for 2 h. The reaction was quenched (10% citric acid),extracted (2×EtOAc) and washed (1×sat. aq. NaCl solution). The combinedorganic layers were washed with sat. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification by reversed phase preparatory HPLC (Gemini™ Prep C18 5 μmcolumn, Phenomenex, Torrance, Calif.; eluent: 35 to 75%acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided thetitle compound as a white foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42-7.37 (3 H, m), 7.34-7.27 (4 H,m), 7.18-7.13 (1 H, m), 4.89 (1 H, d, J=2.7 Hz), 3.99-3.90 (1 H, m),3.78 (1 H, dd, J=11.5, 3.3 Hz), 3.32-3.23 (1 H, m), 3.13-3.07 (1 H, m),2.88-2.65 (3 H, m), 2.35-2.25 (1 H, m), 2.12-2.03 (1 H, m), 1.95-1.84 (1H, m), 1.58-1.46 (1H, m), 0.71 (3 H, t, J=7.4 Hz); MS (ESI) 450.1[M+H]⁺, 448.0 [M−H]⁻.

Example 8

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-ethoxy-2-oxoethyl)-2-oxopiperidin-3-yl)aceticacid (Example 6) as described in Example 7.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.23 (m, 1 H), 0.36 (m, 1 H),0.65-0.69 (m, 2H), 0.95 (m, 1 H), 1.90 (m, 1 H), 2.40 (m, 1 H), 2.68 (m,1 H), 2.80 (2 H, d, J=5.3 Hz), 3.13 (1 H, m), 3.48 (m, 1 H), 3.60-3.85(m, 2 H), 5.32 (s, 1 H), 7.20 (m, 1 H), 7.27-7.40 (m, 3 H), 7.40-7.43(m, 4 H); MS (ESI) 462.1 [M+H]⁺.

Example 9

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid Step A. (S)-Ethyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate

To a solution of 15 g (46.8 mmol) of((5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example1, Step E) in 140 mL of DMF was added 3.75 g (94 mmol) of a dispersionof 60% sodium hydride in mineral oil at 0° C. After being stirred for 20min, ethyl 2-bromobutanoate (17.2 mL, 117 mmol) was added at 0° C. andthe resulting solution was stirred at 25° C. for 12 h until completionof the reaction. Then sat. aq. NH₄Cl solution was added and the mixturewas extracted with ethyl acetate. The combined organic layers werewashed with water and sat. NaCl solution, dried over Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure. Purificationof the residue by flash chromatography on silica gel (eluent: 30%EtOAc/hexanes, gradient elution) provided the title compound as thefaster eluting isomer.

Step B. (S)-Ethyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate

To a solution of 0.62 g (1.4 mmol) of (S)-ethyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate(Example 9, Step A) and allyl bromide (0.14 ml, 1.7 mmol) in THF (6.0mL, 0.25 M) was added lithium bis(trimethylsilyl)-amide (1M solution inTHF, 1.5 ml, 1.5 mmol) at −78° C. The reaction was allowed to warm toR.T., then was quenched (sat. aqueous NH₄Cl) and extracted with EtOAc.The combined organic layers were washed with water and sat. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. Purification of the residue by flashchromatography on silica gel (15 to 20% EtOAc/Hex, gradient elution)provided the title compound as the slower eluting isomer as a colorlessoil.

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

To a solution of 256 mg (0.54 mmol) of (S)-ethyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate(Example 9, Step B) in Et₂O (5.5 mL) was added lithium borohydride of90% purity (17.6 mg, 0.809 mmol) at 0° C. After being stirred at 0° C.for 10 min, the reaction was quenched (ice cold 10% citric acid),extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combinedorganic layers were washed with sat. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification by chromatography on silica gel (eluent 30% to 50%EtOAc/Hexanes, a gradient elution) provided the title compound.

Step D.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one

To a solution of(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(98 mg, 0.227 mmol) in DMF (1.10 mL) was added 60% sodium hydride inmineral oil (27.2 mg, 0.680 mmol) at 0° C. After being stirred at 0° C.for 2 min, (bromomethyl)cyclopropane (47.3 μL, 0.680 mmol) was added.The mixture was stirred at 0° C. for 2 h and then warmed to rt. Then thereaction was stirred at rt overnight. The reaction was quenched (sat aq.NH₄Cl), extracted (2×EtOAc) and washed (sat. aq. NaCl solution). Thecombined organic layer was dried (Na₂SO₄) and concentrated under reducedpressure. Purification by chromatography on silica gel (10% to 20%EtOAc/Hexanes gradient) provided(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-oneas the less polar isomer and the title compound as the more polarstereoisomer.

Step E.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-onewas converted into the carboxylic acid by a procedure similar to the onedescribed in Example 1, Step H. Purification by reversed phasepreparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance,Calif.; eluent: 50 to 80% acetonitrile+0.1% TFA in water+0.1% TFA,gradient elution) provided the title compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39 (2 H, d, J=8.2 Hz), 7.38-7.36(1 H, m), 7.33-7.28 (3 H, m), 7.23 (2 H, d, J=8.2 Hz), 5.09 (1 H, d,J=2.0 Hz), 4.17-4.07 (1 H, m), 3.47-3.40 (2 H, m), 3.23-3.15 (m, 2 H),3.12-3.08 (1 H, m), 2.85 (1 H, dd, J=15.8, 8.8 Hz), 2.66-2.55 (2 H, m),2.22-2.12 (1 H, m), 2.07-1.99 (1 H, m), 1.95-1.85 (1 H, m), 1.62-1.54 (1H, m), 1.07-1.00 (1H, m), 0.65 (3 H, t, J=7.4 Hz), 0.60-0.52 (2 H, m),0.24-0.18 (2 H, m); MS (ESI) 504.1 [M+H]⁺, 502.1 [M−H]⁻.

The following Examples 10 to 12 were prepared from(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 9, Step C) by procedures similar to those described in Example9, Steps D and E, substituting (bromomethyl)cyclopropane in step D forthe appropriate amount of methyliodide, 2-methoxyethylbromide, and1-(bromomethyl)cyclopropanecarbonitrile, respectively.

Example R 10

11

12

Example 10

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52-7.48 (1 H, m), 7.40 (2 H, d,J=8.2 Hz), 7.31-7.28 (2 H, m), 7.27-7.24 (1 H, m), 7.24-7.27 (2 H, m),5.05 (1 H, s), 4.08 (1 H, t, J=9.6 Hz), 3.39 (3 H, s), 3.34 (1 H, dd,J=9.8, 3.1 Hz), 3.20-3.10 (2 H, m), 2.88-2.78 (1 H, m), 2.64-2.55 (2 H,m), 2.25-2.16 (1 H, m), 2.10-2.00 (1 H, m), 1.90-1.81 (1 H, m),1.56-1.50 (1H, m), 0.65 (3 H, t, J=7.4 Hz); MS (ESI) 464.0 [M+H]⁺, 462.1[M−H]⁻.

Example 11

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyethoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41-7.35 (3 H, m), 7.28-7.26 (2 H,m), 7.25-7.21 (3 H, m), 5.09 (1 H, d, J=2.7 Hz), 4.17-4.10 (1 H, m),3.74-3.65 (1 H, m), 3.60-3.52 (3 H, m), 3.44 (1 H, dd, J=10.4, 3.3 Hz),3.35 (3 H, s), 3.25-3.15 (1 H, m), 3.12-3.07 (1 H, m), 2.91-2.80 (1 H,m), 2.71-2.58 (2 H, m), 2.21-2.12 (1 H, m), 2.05-1.89 (2H, m), 1.61-1.52(1 H, m), 0.64 (3 H, t, J=7.6 Hz); MS (ESI) 508.1 [M+H]⁺, 506.0 [M−H]⁻.

Example 12

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyclopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.43-7.30 (3 H, m), 7.28-7.20 (4 H,m), 7.18-7.10 (1 H, m), 5.04 (1 H, d, J=3.9 Hz), 4.13 (1 H, t, J=9.4Hz), 3.52-3.43 (2 H, m), 3.42-3.33 (1 H, m), 3.32-3.24 (1 H, m),3.13-3.05 (1 H, m), 2.92-2.75 (2 H, m), 2.72-2.60 (1 H, m), 2.20-2.10 (1H, m), 2.10-1.90 (1 H, m), 1.64-1.49 (1 H, m), 1.35-1.25 (2 H, m),1.00-0.90 (2 H, m), 0.71-0.57 (3 H, m); MS (ESI) 529.2 [M+H]⁺, 527.0[M−H]⁻.

Examples 13-15 were prepared from(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)piperidin-2-onein a process similar to that described for Example 9, Step D and E.

Example R¹ 13

14

15

Example 132-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d, J=8.6 Hz), 7.22-7.18(1 H, m), 7.15-7.11 (1 H, m), 7.08-7.04 (1 H, m), 6.96 (2 H, d, J=8.6Hz), 6.77-6.73 (1 H, m), 4.69 (1 H, d, J=10.2 Hz), 4.03 (1 H, t, J=9.8Hz), 3.42-3.33 (2 H, m), 3.28-3.22 (1 H, m), 3.10-2.90 (4 H, m), 2.50 (1H, dd, J=15.3, 3.1 Hz), 2.20-2.10 (1 H, m), 2.01-2.01 (1 H, m),1.92-1.80 (1 H, m), 1.65-1.53 (1 H, m), 1.16-1.08 (1 H, m), 0.66-0.60 (2H, m), 0.53 (3 H, t, J=7.6 Hz), 0.28-0.24 (2 H, m); MS (ESI) 504.1[M+H]⁺, 502.1 [M−H]⁻.

Example 142-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J=7.53 Hz, 3 H), 1.49-1.60(m, 1 H), 1.77-1.91 (m, 1 H), 2.02-2.15 (m, 2 H), 2.51 (dd, J=15.26,3.33 Hz, 1 H), 2.89-2.99 (m, 1 H), 2.99-3.09 (m, 2 H), 3.09-3.17 (m, 1H), 3.29 (dd, J=9.68, 4.21 Hz, 1 H), 3.34 (s, 3 H), 3.90 (t, J=9.49 Hz,1 H), 4.57 (d, J=9.98 Hz, 1 H), 6.75 (d, J=7.43 Hz, 1 H), 6.97 (d,J=8.41 Hz, 2 H), 7.00 (t, J=1.76 Hz, 1 H), 7.14 (t, J=7.73 Hz, 1 H),7.17-7.22 (m, 1 H), 7.25 (d, J=8.41 Hz, 2 H).

Example 152-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methoxyethoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J=8.2 Hz), 7.21-7.16(1 H, m), 7.14-7.09 (1 H, m), 7.05-7.03 (1 H, m), 6.97 (2 H, d, J=8.2Hz), 6.75-6.71 (1 H, m), 4.66 (1 H, d, J=10.6 Hz), 4.09 (1 H, t, J=9.8Hz), 3.70-3.55 (4 H, m), 3.47 (3 H, s), 3.44 (1 H, dd, J=9.8, 4.3 Hz),3.05-2.90 (4 H, m), 2.53 (1 H, dd, J=15.1, 2.5 Hz), 2.28-2.15 (1 H, m),2.05-1.97 (1 H, m), 1.92-1.82 (1 H, m), 1.65-1.55 (1 H, m), 0.50 (3 H,t, J=7.6 Hz); MS (ESI) 508.1 [M+H]⁺, 506.0 [M−H]⁻.

Example 16

2-((3R,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid

A solution of 10 mg (0.02 mmol)2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((1-cyanocyclopropyl)methoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (Example 11) and potassium hydroxide (3.2 mg, 0.06 mmol) in t-BuOH(189 μL) was stirred at 85° C. for 24 h. The reaction was acidified (10%citric acid) and extracted (2×EtOAc). The combined organic layers werewashed with sat. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification byreversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column,Phenomenex, Torrance, Calif.; eluent: 35 to 75% acetonitrile+0.1% TFA inwater+0.1% TFA, gradient elution) provided the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.67 (m, 5 H), 1.34 (m., 2 H), 1.54(m., 1 H), 1.87-2.18 (m, 4 H), 2.65 (m, 1 H), 2.71-2.90 (m, 2 H), 3.08(m, 1 H), 3.38-3.64 (m, 4 H), 3.94 (m, 1 H), 4.84 (m, 1 H),6.35 (br.s.,1 H), 6.91 (br. s., 1 H) 7.13 (m, 1 H) 7.21-7.38 (m, 7 H). MS (ESI)547.2 [M+H]⁺, 545.0 [M−H]⁻.

Further elution provided Example 17.

Example 17

2-((3S,5R,6S)-1-((S)-1-((1-carbamoylcyclopropyl)methoxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.26-7.21 (2 H, m), 7.17-7.12 (2 H,m), 7.06 (1 H, br, s), 6.95-6.90 (2 H, m), 6.88-6.80 (1 H, s), 6.79-6.76(1 H, m), 6.74 (1 H, br, s), 4.63 (1 H, d, J=10.2 Hz), 4.10-4.00 (1H,m), 3.33-3.10 (3 H, m), 3.02-2.92 (2 H, m), 2.90-2.78 (1 H, m),2.70-2.60 (1 H, m), 2.44-2.34 (1 H, m), 2.00-1.90 (1 H, m), 1.85-1.75 (1H, m), 1.65-1.55 (1 H, m), 1.43-1.35 (2 H, m), 0.85-0.73 (2 H, m),0.63-0.52 (3 H, m); MS (ESI) 547.2 [M+H]⁺, 545.0 [M−H]⁻.

Example 18

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid Step A. Ethyl2-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butoxy)acetate

To a solution of 203 mg (0.47 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 9, Step B) and rhodium(II)acetate dimmer (10.4 mg, 0.047 mmol)in CH₂Cl₂ (1.90 mL) was added dropwise ethyl diazoacetate (286 μL, 2.35mmol) at 25° C. After being stirred at 25° C. for 14 h, the reaction wasconcentrated under reduced pressure and purified by chromatography onsilica gel (20% to 30% EtOAc/Hexanes, gradient elution) to provide thetitle compound as a colorless liquid:

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropoxy)butan-2-yl)piperidin-2-one

To a solution of ethyl2-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butoxy)acetate(69.0 mg, 0.133 mmol) in THF (2.22 mL) was added methylmagnesiumbromide, 1.4M in Toluene/THF, (0.38 mL, 0.532 mmol) at 0° C. After beingstirred at 25° C. for 3 h, the reaction was quenched (sat. aq. NH₄Cl),and extracted with EtOAc. The combined organic layers were washed withsat. NaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification by chromatography onsilica gel (20% to 50% EtOAc/Hexanes, gradient elution) provided thetitle compound as a colorless liquid.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropoxy)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a rapidly stirring solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropoxy)butan-2-yl)piperidin-2-one (51.0 mg, 0.101 mmol) in a mixture ofwater (361 μL), acetonitrile (241 μL), and CCl₄ (241 μL) was addedsodium periodate (86 mg, 0.404 mmol), followed by ruthenium(III)chloride hydrate (2.28 mg, 10.1 μmol). After being stirred vigorouslyfor 18 h, the reaction was acidified (10% citric acid) and diluted(EtOAc). The mixture was filtered through Celite® (J.T. Baker,Phillipsberg, N.J., J.T. Baker, Phillipsberg, N.J., diatomaceous earth)and the filtrate was extracted with EtOAc. The combined organic layerswere washed with sat. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification byreversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column,Phenomenex, Torrance, Calif.; eluent: 50 to 76% acetonitrile+0.1% TFA inwater+0.1% TFA, gradient elution) provided the title compound as a whitesolid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.64-0.74 (t, J=7.6 Hz, 3 H), 1.21(d, J=3.7 Hz, 6 H), 1.58 (ddd, J=14.0, 7.6, 4.4 Hz, 1 H), 1.84-1.99 (m,2 H), 2.21 (m, 1 H), 2.64-2.83 (m, 3 H), 3.04-3.15 (m, 1 H), 3.19 (d,J=9.2 Hz, 1 H), 3.29 (d, J=9.2 Hz, 1 H), 3.38 (m, 1 H), 3.41-3.55 (m,1H), 3.98 (t, J=8.6 Hz, 1H), 4.98 (d, J=2.9 Hz, 1 H) 7.12-7.20 (m, 1 H),7.21-7.34 (m, 5 H), 7.34-7.41 (m, 2 H); MS (ESI) 522.1 [M+H]⁺. 520.2[M−H]⁻.

Example 19

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)aceticacid (Isomer 1) Step A.(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal

To a solution of oxalyl dichloride (166 μL, 1.87 mmol) in DCM (4.16 mL)at −60° C. was added a solution of DMSO (222 μL, 3.12 mmol) in DCM (4.16mL) under N₂. After about 20 min, a solution of 540 mg (1.25 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 9, Step B) in 4.2 mL of DCM was added, and the resultingsolution was stirred for 15 min. Triethylamine (872 μL, 6.24 mmol) wasthen added. After being stirred at −60° C. for 5 min, the reaction wasallowed to warm to rt, and 5 mL of water was added. The solution wasextracted (2×DCM), washed (sat. aq. NaCl solution), dried (MgSO₄) andconcentrated under the reduced pressure to give the crude title compoundcontaining 20% starting material (SM).

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-2-one

A solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal(80 mg, 0.186 mmol) and trimethyl(trifluoromethyl)silane (82 μL, 0.558mmol) in THF (929 μL) was treated at 0° C. with 1 M tetrabutylammoniumfluoride in THF (93 μL, 0.093 mmol). After being stirred for 1 h, threeadditional equivalents of trimethyl(trifluoromethyl)silane (82 μL, 0.558mmol) and 1 M tetrabutylammonium fluoride in THF (93 μL, 0.093 mmol)were added to the reaction at 0° C. and the reaction was stirred for 14h. The reaction mixture was diluted (EtOAc), washed (1×H₂O and 1×sat.aq. NaCl solution), dried (Na₂SO₄), and concentrated under reducedpressure. Purification by reverse phase preparatory HPLC (Gemini™ PrepC18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 60 to 90%acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) provided twocompounds which are diastereomers at the secondary alcohol.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)aceticacid

The title compound was prepared from a single diastereomer of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-2-oneby a procedure similar to the one described in Example 18, Step C.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.53 (t, J=7.5 Hz, 3 H), 1.66 (m, 1H), 1.97-2.05 (m, 1 H), 2.18 (m, 1 H), 2.32-2.45 (m, 1 H), 2.68-2.83 (m,2 H), 2.94-3.05 (m, 1 H), 3.15-3.25 (m, 1 H), 4.42 (m, 1 H), 4.69 (d,J=3.9 Hz, 1 H), 6.95-7.02 (m, 1 H), 7.12 (m, 1 H), 7.22-7.37 (m, 5 H),7.37-7.46 (m, 2 H); MS (ESI) 518.0 [M+H]⁺. 516.0 [M−H]⁻.

Example 20

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-3-yl)aceticacid (Isomer 2)

To a rapidly stirring solution of 6.3 mg (0.013 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,1,1-trifluoro-2-hydroxypentan-3-yl)piperidin-2-one(Example 19, Step B, the diastereomer not used for Example 19 Step B))(6.30 mg, 0.013 mmol) in a mixture of water (108 μL), acetonitrile (71.9μL), and CCl₄ (71.9 gt) was added sodium periodate (10.7 mg, 0.050mmol), followed by ruthenium(III) chloride hydrate (0.284 mg, 1.26μmol). After being stirred vigorously for 18 h, the reaction wasacidified (10% citric acid) and diluted (EtOAc). The reaction mixturewas filtered through Celite® (J.T. Baker, Phillipsberg, N.J., J.T.Baker, Phillipsberg, N.J., diatomaceous earth). The filtrate wasextracted (2×EtOAc). The combined organic layers were washed with sat.NaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification by reversed phasepreparatory HPLC (Gemini™ Prep C18 5 μm column, Phenomenex, Torrance,Calif.; eluent: 45 to 70% acetonitrile+0.1% TFA in water+0.1% TFA,gradient elution) provided the title compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.44-0.72 (m, 3 H); 1.28-1.46 (m, 1H), 2.15-2.28 (m, 2 H), 2.45-2.55 (m, 1 H), 2.89-3.05 (m, 3 H),3.10-3.18 (m, 2 H), 4.02-4.16 (m, 1 H), 4.56 (d, J=7.8 Hz, 1 H),6.84-6.93 (m, 1 H), 7.01-7.04 (m, 1 H), 7.08-7.14 (m, 2 H), 7.17-7.20(m, 2 H), 7.32-7.38 (m, 2 H); MS (ESI) 518.0 [M+H]⁺. 516.0 [M−H]⁻.

Example 21

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A. (S)-ethyl2-((3R,5R,6S)-3-(2-tert-butoxy-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate

To a stirred solution of 1.14 g (2.3 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid (Example 3) in DCM (21.0 mL) was added sulfuric acid (0.247 mL,4.63 mmol) followed by isobutylene (4.42 mL, 46.3 mmol) at −78° C. Thereaction vessel was sealed and the mixture was slowly warmed to rt andvigorously stirred for 3 days. After cooling to −78° C., the tube wasopened and the reaction was quenched with aqueous saturated NaHCO₃ to pH8. The organic solvent was removed under reduced pressure, and theremaining mixture was extracted (2×EtOAc). The combined organic layerswere washed with sat. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by chromatography on silica gel (eluent: 20 to 35%EtOAc/hexanes) to provide the title compound as a foam.

Step B. tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)acetate

To a solution of (S)-ethyl2-((3R,5R,6S)-3-(2-tert-butoxy-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate(1.94 g, 3.54 mmol, Example 21, Step A) in Et₂O (35.4 mL) was added 90%lithium borohydride (0.154 g, 7.07 mmol) at 0° C. After being stirred at0° C. for 30 min, the reaction was quenched (ice cold 10% citric acid),extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combinedorganic layers were washed with sat. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification by chromatography on silica gel (50% to 100% EtOAc/Hexanes,gradient elution) provided the title compound.

Step C. tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetate

To a solution of oxalyl chloride (0.261 mL, 2.99 mmol) in DCM (5.87 mL)at −60° C. was added a solution of DMSO (0.512 mL, 5.98 mmol) in DCM(5.87 mL) under N₂. After being stirred for 20 min, a solution oftert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)acetate(1.01 g, 1.99 mmol, Example 21, Step B) in DCM (5.87 mL) was added, andthe resulting solution was stirred for 15 min. To this solution wasadded triethylamine (1.39 mL, 9.97 mmol). After being stirred at −60° C.for 5 min, the reaction was allowed to warm to rt, and quenched (H₂O).The solution was extracted (3×DCM) and washed (H₂O and sat. aq. NaClsolution). The combined organic layers were washed with sat. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure to give the title compound.

Step D. tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetate

To a solution of tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetate(0.050 g, 0.099 mmol, Example 21, Step C) and morpholine (0.013 mL,0.149 mmol) in DCE (1.0 mL) was added sodium triacetoxyhydroborate(0.063 g, 0.297 mmol) at 0° C. After being stirred at 25° C. for 18 h,the reaction was quenched by adding ice-cold saturated aqueous NaHCO₃and extracted (2×DCM) and the combined organic layers were washed(1×sat. aq. NaCl solution) and concentrated under the reduced pressure.This was used in next step without further purification.

Step E.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a round-bottomed flask with tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetate(0.057 g, 0.099 mmol; Example 21, Step D) in DCM (1 mL) was added TFA(1.129 g, 9.90 mmol) at 0° C. The ice-bath was removed and the mixturewas stirred at rt for 3 h. The solvent was removed. Purification byreversed phase preparatory HPLC (Gemini™ Prep C18 5 μm column,Phenomenex, Torrance, Calif.; eluent: 10 to 90% acetonitrile+0.1% TFA inwater+0.1% TFA, gradient elution) provided the title compound as a whitepowder.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (m, 3 H), 1.60-2.43 (m., 4 H),2.60-2.86 (m, 5 H), 3.11-3.40 (m, 2 H), 3.83-4.04 (m, 5 H), 4.43 (m, 2H), 4.90 (m, 1 H), 7.01 (m, 1 H) 7.12 (m, 1 H) 7.20-7.36 (m, 2 H) 7.46(m., 4H); MS (ESI) 519.1 [M+H]⁺. 517.2 [M−H]⁻

Examples 22 to 27 were prepared in a process similar to that describedfor Example 21, substituting morpholine in step D for the appropriateamine.

Example R¹ 22

23

24

25

26

27

Example 222-((3RS,5RS,6SR)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(ethylamino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (prepared from racemic intermediate)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.91-1.13 (t, J=7.8 Hz, 3 H), 1.28(t, J=7.14 Hz, 3 H), 1.55-1.65 (m, 1 H), 1.76-1.86 (m, 1 H), 1.95-2.05(m, 1 H), 2.31-2.59 (m, 2 H), 2.73-2.85 (m, 2 H), 2.90-3.09 (m, 5 H),4.78-4.82 (m, 1 H), 4.88-5.02 (m, 1 H), 6.90-6.98 (m, 1 H), 7.04-7.12(m, 1 H), 7.20-7.30 (m, 3 H), 7.36-7.42 (m, 2 H), 7.45-7.56 (m, 1H); MS(ESI) 477.1 [M+H]⁺, 475.1 [M−H]⁻.

Example 232-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J=7.3 Hz, 3 H), 1.62-1.74(m, 1 H), 1.79-1.98 (m, 2 H), 2.41-2.51 (m, 1 H), 2.61-2.75 (m, 2 H),3.01-3.21 (m, 4 H), 3.74-3.91 (m, 2 H), 4.57 (m, 1 H), 4.89 (d, J=2.9Hz, 1 H), 6.96-7.02 (m, 1 H), 7.12 (m, 1 H), 7.24-7.31 (m, 2 H),7.36-7.49 (m, 4 H); MS (ESI) 531.1 [M+H]⁺, 529.0 [M−H]⁻.

Example 242-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93 (m., 3 H), 1.67-1.75 (m, 2 H),2.03-2.39 (m., 7 H), 2.74-2.91 (m, 6 H), 3.09-3.17 (m, 2 H), 3.86 (m, 1H), 4.05 (m, 1 H), 4.86 (m, 1 H), 6.82-7.04 (m, 1 H) 7.09 (m, 1 H) 7.25(m, 2 H) 7.44 (m, 4 H); MS (ESI) 503.2 [M+H]⁺, 501.1 [M−H]⁻.

Example 252-((3RS,5RS,6SR)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((SR)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)aceticacid (Prepared from Racemic Intermediate

Ethyl 4-aminobutanoate hydrochloride was used at the amine. Afterreductive amination the intermediate was cyclized by heating to 120° C.in acetic acid and toluent to provide the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93 (m., 3 H), 1.67 (m, 1 H), 1.82(m, 1 H), 2.07-2.20 (m., 5 H), 2.44-2.46 (m, 3 H), 2.71-3.06 (m, 3 H),3.20-3.30 (m, 2 H), 3.40-3.55 (m, 3 H), 3.69 (m, 1 H), 4.70 (m, 1 H),6.99-7.04 (m, 1 H) 7.12-7.16 (m, 3 H) 7.24-7.27 (m, 2 H) 7.35 (m, 2 H);MS (ESI) 517.2 [M+H]⁺.

Example 262-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidothiomorpholino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.85 (m., 3 H) 1.71 (m, 2 H)1.83-1.98 (m, 1 H) 2.37 (m, 1 H) 2.58 (m, 1 H) 2.63-2.83 (m, 2 H)3.04-3.15 (m, 3 H), 3.25-3.35 (m., 6 H) 3.43-3.64 (m, 2 H) 4.88 (m, 1 H)7.09 (m., 1 H) 7.19 (m, 1 H) 7.29 (m, 2 H) 7.34-7.50 (m, 4 H); MS (ESI)567.1 [M+H]⁺, 565.2 [M−H]⁻.

Example 272-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(thiazol-2-ylamino)butan-2-yl)piperidin-3-yl)aceticacid

¹H NMR (500 MHz, ACETONITRILE-d₃) δ ppm 0.58 (t, J=7.2 Hz, 3 H),1.52-1.64 (m, 1 H), 1.73-1.89 (m, 1 H), 1.98-2.05 (m, 1 H), 2.05-2.16(m, 1 H), 2.67-2.81 (m, 1 H), 2.81-2.92 (m, 2 H), 3.11-3.32 (m, 2 H),3.50 (m, 1 H), 3.68 (m, 1 H), 4.81 (d, J=6.8 Hz, 1 H), 6.72-6.79 (m, 1H), 7.04-7.12 (m, 1 H), 7.14 (s, 1 H), 7.17-7.23 (m, 2 H), 7.25 (d,J=4.4 Hz, 1 H), 7.29-7.41 (m, 4 H); MS (ESI) 530.0 [M−H]⁻.

Example 28

2-((3RS,5RS,6SR)-1-((SR)-1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid (racemic) Step A.(3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(4-methoxybenzylamino)butan-2-yl)piperidin-2-one

To a solution of 79 mg (0.184 mmol) of(SR)-2-((3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal(racemate of Example 19, Step A) and 4-methoxybenzylamine (35.7 μL,0.275 mmol) in 1.8 mL of dichloroethane was added sodiumtriacetoxyborohydrate (117 mg, 0.551 mmol)at 0° C. in several portions.After being stirred at 25° C. for 18 h, the reaction was quenched byadding ice-cold saturated aqueous NaHCO₃ and extracted (2×DCM) and thecombined organic layers were washed with sat. NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. Purification by flash chromatography on silica (0% to 3%MeOH/DCM with 1% aq. NH₄OH) provided the title compound as a yellowfilm.

Step B.(3SR,5RS,6SR)-3-allyl-1-((SR)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one

To a solution of(3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((SR)-1-(4-methoxybenzylamino)butan-2-yl)piperidin-2-one(88 mg, 0.160 mmol) in acetonitrile (1899 μL) and water (380 μL) wasadded ceric ammonium nitrate (350 mg, 0.638 mmol) at 25° C.

The reaction was monitored by LCMS and HPLC and on completion wasdiluted with 0.5 M aq. NaOH and EtOAc and the resulting emulsion wasfiltered through a pad of Celite® (J.T. Baker, Phillipsberg, N.J., J.T.Baker, Phillipsberg, N.J., diatomaceous earth). The fitrate wasextracted with ethyl acetate and the combined organic layers were washedwith sat. NaCl solution, dried over Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure to provide the crude productwhich was used n subsequent steps without further purification.

Step C.N—(SR)-2-((3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butyl)acetamide

To a solution of 53 mg (0.123 mmol) of(3SR,5RS,6SR)-3-allyl-1-((RS)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Step B) in DMF (307 μL) was added acetic anhydride (116 μL, 1.229 mmol)at 25° C. After being stirred at 25° C. for 14 h the reaction wasquenched (H₂O) and extracted (2×EtOAc). The combined organic layers werewashed with sat. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Separation by reversedphase HPLC (50 to 80% AcCN/H₂O in 25 min, 2 injections, t_(R)=15.683min) provided the title compound as a yellow solid.

Step D.2-((3RS,5RS,6SR)-1-((SR)-1-acetamidobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid

The oxidation ofN—((SR)-2-((3SR,5RS,6SR)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butyl)acetamideto the title compound was carried out as described in Example 1, Step Hto give the title compound as white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.80 (t, J=7.4 Hz, 3 H,) 1.62-1.75(m, 1 H), 1.84-1.97 (m, 2 H), 2.07 (s, 3 H), 2.36-2.49 (m, 1 H),2.64-2.80 (m, 2 H), 3.02-3.16 (m, 2 H), 3.16-3.31 (m, 1 H), 3.32-3.40(m, 1 H), 3.74-3.90 (m, 1 H), 4.76-4.82 (m, 1 H), 7.04-7.08 (m, 1 H),7.16-7.19 (m, 1 H), 7.22-7.30 (m, 2 H), 7.32-7.38 (m, 4 H); MS (ESI)491.0 [M+H]⁺, 489.1 [M−H]⁻.

Example 29

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butyl)methanesulfonamide

To a solution of 69 mg (0.16 mmol) of(3S,5R,6S)-3-allyl-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 28, Step B from the non-racemic precursor described in Example19, Step A) in 1.6 mL of DCM was added methanesulfonyl chloride (13.7μL, 0.175 mmol) and pyridine (38.7 μL, 0.478 mmol) successively at 0° C.After being stirred at rt for 14 h the reaction mixture was acidifiedwith 10% aq. citric acid and extracted (2×DCM). The combined organiclayers were washed with sat. NaCl solution, dried over Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure. Purificationby reversed phase HPLC (40 to 90% MeCN/H₂O in 45 min, 2 injections,t_(R)=25.94 min) provided the title compound as a yellow solid.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetic acid

The title compound was prepared as described in Example 28, Step D,usingN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butyl)methanesulfonamide(Step A).

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.67 (t, J=7.6 Hz, 3 H), 1.51-1.61(m, 1 H), 1.88-1.92 (m, 1 H), 2.13-2.26 (m, 2 H), 2.79-2.89 (m, 2 H),2.89-2.95 (m, 1 H), 2.98 (s, 3 H), 3.02-3.10 (m, 1 H), 3.17-3.21 (m, 1H), 3.42-3.52 (m, 1 H), 4.85 (d, J=5.4 Hz, 1 H), 5.27 (br. s., 1 H),7.02-7.10 (m, 1 H), 7.10-7.15 (m, 1 H), 7.18-7.30 (m, 4 H), 7.34 (d,J=8.6 Hz, 2 H); MS (ESI) 527.0 [M+H]⁺, 525.1 [M−H]⁻.

Example 30

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)aceticacid Step A. tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopent-1-en-3-yl)-2-oxopiperidin-3-yl)acetate

To a solution of diethyl cyanomethylphosphonate (62.4 μL, 0.396 mmol)and DMPU (239 μL, 1.98 mmol) in THF (661 μL) was added 60% sodiumhydride as a suspension in mineral oil (11.89 mg, 0.297 mmol) at 0° C.The mixture was stirred for 30 min, and then treated with a solution of100 mg (0.2 mmol) of tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((R)-1-oxobutan-2-yl)piperidin-3-yl)acetate(Example 21, Step C) in THF (661 μL). After being stirred for 12 h, thereaction was quenched with water, extracted (2×EtOAc) and the combinedorganic layers were washed with sat. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification of the residue by flash chromatography on silica gel (10 to20% EtOAc/Hex, a gradient elution) provided the of the title compound asa mixture of E- and Z-isomers.

MS (ESI) 527.2 [M+H]⁺.

Step B. tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)acetate

To a solution of 56 mg (0.106 mmol) of tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopent-1-en-3-yl)-2-oxopiperidin-3-yl)acetate(Example 30, Step A) in 3.5 mL of EtOH) was added 10% palladium onactivated carbon (11.30 mg, 10.62 μmol).

Then the reaction mixture was subjected to regular hydrogenation withhydrogen. After being stirred under a hydrogen atmosphere at rt for 2 h,the catalyst was filtered using a short plug of silica gel. The plug waswashed several times with EtOAc. The combined filtrates wereconcentrated under reduced pressure to provide the crude title compoundas a colorless film which was used in the subsequent reaction withoutfurther purification. MS (ESI) 529.2 [M+H]+.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of 57 mg (0.11 mmol) of tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyanopentan-3-yl)-2-oxopiperidin-3-yl)acetate(Example 30, Step B) in DCM (359 μL) was added trifluoroacetic acid (415μL, 5.38 mmol) at 0° C. After being stirred at 25 C for 2 h, solventswere removed under reduced pressure and the residual TFA was removed byazeotroping with toluene under reduced pressure three times. Separationof the crude product by reversed phase HPLC (45 to 70% AcCN/H₂O in 30min, 3 time runs, t_(R)=18.52 min) provided the title compound as awhite solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37 (2 H, d, J=8.6 Hz), 7.27-7.25(2 H, m), 7.21 (2 H, d, J=8.6 Hz), 7.15-7.12 (1 H, m), 7.04-6.98 (1 H,m), 4.74 (1 H, d, J=5.3 Hz), 3.42-3.32 (1 H, m), 3.13-3.08 (1 H, m),3.08-3.00 (1 H, m), 2.99-2.92 (1 H, m), 2.85-2.77 (1 H, m), 2.43-2.33 (2H, m), 2.23-2.15 (2 H, m), 2.13-2.03 (1 H, m), 1.94-1.77 (2 H, m),1.64-1.54 (1 H, m), 0.64 (3 H, t, J=7.4 Hz); MS (ESI) 473.0 [M+H]⁺,471.1 [M−H]⁻.

Examples 31 and 32 were prepared in a process similar to that describedfor Example 30, using the appropriately substituted phosphonates in StepA:

Example 31

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.71 (t, J=8.0 Hz, 3 H), 1.58-1.69(m, 1 H), 1.82 (m, 1 H), 1.98-2.17 (m, 3 H), 2.20-2.34 (m, 1 H),2.83-3.13 (m, 10 H), 4.80-4.84 (m, 1 H), 7.00-7.07 (m, 1 H), 7.13-7.18(m, 1 H), 7.23-7.32 (m, 4 H), 7.34-7.41 (m, 2 H); MS (ESI) 526.2 [M+H]⁺.

Example 32

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-((S)-1-(pyridin-2-yl)pentan-3-yl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.89 (t, J=7.5 Hz, 3 H), 1.60-1.79(m, 4 H), 1.90-1.98 (m, 1 H), 2.53 (m, 1 H), 2.61-2.69 (m, 1 H),2.72-2.79 (m, 1 H), 2.90-3.03 (m, 2 H), 3.07-3.12 (m, 1 H), 3.19-3.28(m, 1 H), 4.15 (m, 1 H), 4.80-4.81 (m, 1 H), 7.01-7.07 (m, 1 H), 7.15(s, 1 H), 7.22-7.35 (m, 4 H), 7.40-7.47 (m, 1 H), 7.59 (d, J=7.82 Hz, 1H), 7.75 (t, J=6.75 Hz, 1 H), 8.28 (t, J=7.92 Hz, 1 H), 8.85-8.89 (m, 1H); MS (ESI) 525.1 [M+H]⁺

Example 33

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid and2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(ethylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid Step A.(R)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoicacid

To a solution of 320 mg (0.64 mmol) of tert-butyl(2S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate(Example 1, Step G) in DCM (3184 μL) was added trifluoroacetic acid(2453 μL, 31.8 mmol) at 0° C. After being stirred at 25 C for 3 h,solvents were removed under reduced pressure and the residual TFA wasremoved by azeotroping with toluene under reduced pressure 3-times toprovide the title compound as a pale yellow foam which was used in thesubsequent reaction without further purification.

Step B.(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)-N-ethylbutanamide

A solution of 107 mg (0.24 mmol) of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoicacid (Example 33, Step A) and ethylamine (31.4 μL, 0.479 mmol) in DCM(539 μL) and DMF (59.9 μL) was treated at 0° C. withN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (138 mg, 0.719 mmol),3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (98 mg, 0.719 mmol), and sodiumbicarbonate (60.4 mg, 0.719 mmol), successively. Then the reaction wasstirred at 25° C. for 12 h. The reaction was diluted (1 N aq. HCl),extracted (2×EtOAc), the combined organic layers were washed with sat.aq. NaCl and NaHCO₃-solutions, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification bychromatography on silica gel (30% to 40% EtOAc/Hexanes, a gradientelution) provided the title compound as a mixture of diastereomers(dr=5:1) as a white solid: MS (ESI) 473.2 [M+H]⁺.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid and2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(ethylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)-N-ethylbutanamide(Example 33, Step B) was converted to the acid as described in Example1, Step H to give the title compounds as a mixture of diastereomers(dr=5:1).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.81 (t, J=7.8 Hz, 3 H), 1.10 (t,J=7.2 Hz, 3 H), 1.65-1.75 (m, 1 H), 1.87 (m, 1 H), 2.24-2.41 (m, 2 H),2.57-2.66 (m, 1 H), 2.70 (dd, J=16.8, 5.09 Hz, 1 H), 2.98 (dd, J=16.9,5.58 Hz, 1 H), 3.04-3.26 (m, 3 H), 3.97 (dd, J=10.37, 4.89 Hz, 1 H),5.05-5.10 (m, 1 H), 7.06-7.19 (m, 2 H), 7.19-7.24 (m, 1 H) 7.24-7.38 (m,5 H); MS (ESI) 491.0 [M+H]⁺. 489.1 [M−H]⁻.

Example 34

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid and2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid Step A.(S)—N′-acetyl-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanehydrazide

A solution of 95 mg (0.213 mmol) of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoicacid (Example 33, Step A) and acetic hydrazide (23.65 mg, 0.319 mmol) inDCM (479 μL) and DMF (53.2 μL) was treated at 0° C. withN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (122 mg, 0.638 mmol),3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (87 mg, 0.638 mmol), and sodiumbicarbonate (53.6 mg, 0.638 mmol) at 0° C., successively. Then thereaction was stirred at 25° C. for 12 h. The reaction was diluted with 1N aq. HCl and extracted (2×EtOAc). The combined organic layers werewashed with sat. aq. NaCl and NaHCO₃-solutions, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification by chromatography on silica gel (60% to 80% EtOAc/Hexanes,gradient elution) provided the title compound as a colorless film. MS(ESI) 502.1 [M+H]⁺.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl)piperidin-2-one

A solution of 58 mg (0.115 mmol) of(S)—N′-acetyl-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanehydrazide(Example 34, Step A) and Burgess' reagent (110 mg, 0.462 mmol) indichloroethane (1154 μL) was heated in the microwave at 120° C. for 30min. Then the reaction mixture was diluted with water and extracted withDCM. The combined organic layers were washed with sat. aq. NaCl andNaHCO₃-solutions, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. Separation by reversed phase HPLC(55 to 90% MeCN/H₂O in 35 min, 29 mg injection each time) provided thetitle compound as a colorless film. MS (ESI) 484.1 [M+H]⁺.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5-methyl-1,3,4-oxadiazol-2-yl)propyl)piperidin-2-one(Example 34, Step B) was converted to the acid as described in Example1, Step H to give the title compound as a mixture of diastereomers(dr=10:1).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.81 (t, J=7.8 Hz, 3 H), 1.93-2.04(m, 2 H), 2.25 (m, 1 H), 2.26 (s, 3 H), 2.33-2.44 (m, 1 H), 2.83-2.94(m, 3 H), 3.12 (d, J=2.3 Hz, 1 H), 5.08-5.18 (m, 1 H), 5.60 (br. s., 1H), 7.07 (d, J=8.2 Hz, 2 H), 7.18-7.23 (m, 1 H), 7.26 (m, 1 H), 7.28 (m,1 H), 7.30-7.35 (m, 3 H); MS (ESI) 502.1 [M+H]⁺, 500.0 [M−H]⁻.

Example 35

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid Step A.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

To a solution of 1.5 g (4.7 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1,Step E) in 9.4 mL of DMF was added sodium hydride (60% suspension inmineral oil, 244 mg, 6.1 mmol) at 0° C. The reaction was stirred at 0°C. for 20 min and then treated with cyclopropylmethyl bromide (759 μl,5621 μmol).

After being stirred at 25° C. for 5 h, the reaction was quenched (sat.aqueous NH₄Cl), extracted (2×EtOAc). The combined organic layers werewashed with sat. aq. NaCl and NaHCO₃-solutions, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification of the residue by flash chromatography on silica gel (30 to50% EtOAc/hexanes, gradient elution) provided the title compound as acolorless foam.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

To a solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one(1481 mg, 3957 μmol; Example 35, Step A) and allyl bromide (360 μl, 4155μmol) in THF (16 mL, 0.25 M) was added dropwise lithiumbis(trimethylsilyl)amide (1M solution in THF, 4352 μl, 4352 μmol) at−78° C. After being stirred at −78° C. for 3 h, the reaction wasquenched (sat. aqueous NH₄Cl), extracted (2×EtOAc). The combined organiclayers were washed with sat. aq. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification of the residue by flash chromatography (SiO₂, 20 to 30%EtOAc/Hex, gradient elution) provided the title compound as a mixture ofstereoisomers.

Individual stereoisomers were separated by HPLC on a Chiralcel OD column(eluent: 25% iPA/hexanes).

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one(Example 35, Step B) was converted to the acid as described in Example1, Step H to give the title compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.48-7.46 (1 H, m), 7.40 (2 H, d,J=8.6 Hz), 7.31-7.35 (2 H, m), 7.22-7.26 (1 H, m), 7.13 (2 H, d, J=8.6Hz), 5.17 (1 H, s), 4.24 (1 H, dd, J=14.1, 6.7 Hz), 3.23-3.19 (1 H, m),2.96-2.78 (1 H, m), 2.64-2.50 (2 H, m), 2.36 (1 H, dd, J=14.1, 7.8 Hz),2.17-2.08 (1 H, m), 1.93-1.83 (1 H, m), 1.29-1.17 (1 H, m), 0.77-0.69 (1H, m), 0.67-0.58 (1 H, m), 0.37-0.25 (2 H, m); MS (ESI) 432.1 [M+H]⁺,429.9 [M−H]⁻.

Examples 36 to 40 were prepared in a process similar to that describedfor Example 35, substituting (bromomethyl)cyclopropane in Step A for theappropriate amount of alkylbromide or alkyliodide.

Example R¹ 36

37

38

39

40

Example 362-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CDCl₃) δ ppm 1.62-1.74 (m, 1 H), 1.75-1.84 (m, 2 H),1.84-2.01 (m, 2 H), 2.03-2.17 (m, 2 H), 2.18-2.29 (m, 1 H), 2.53 (dd,J=13.69 and 7.24 Hz, 1 H), 2.57-2.63 (m, 1 H), 2.63-2.70 (m, 1 H),2.69-2.76 (m, 1 H), 2.76-2.85 (m, 1 H), 3.04-3.17 (m, 1 H), 4.25 (dd,J=13.69 and 7.63 Hz, 1 H), 4.76-4.89 (m, 1 H), 7.07-7.17 (m, 1 H), 7.22(d, J=8.61 Hz, 2 H), 7.27-7.31 (m, 3 H), 7.39 (d, J=8.61 Hz, 2 H). MS(ESI) 446.2 [M+H]⁺.

Example 372-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-ethylbutyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37 (2 H, d, J=8.4 Hz), 7.27 (2 H,m), 7.18 (1 H, s), 7.15 (2 H, d, J=8.4 Hz), 7.03 (1 H, m), 4.67 (1 H, d,J=7.5 Hz), 3.29 (1 H, m), 3.09-2.97 (3 H, m), 2.72 (1 H, dd, J=15.4, 3.7Hz), 2.20-2.00 (2 H, m), 1.83 (1 H, m), 1.68 (1 H, m), 1.55-1.40 (2 H,m), 0.89 (3 H, t, J=8.0 Hz), 0.55 (3 H, t, J=8 Hz); MS (ESI) 448.1 [MH]⁻.

Example 382-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42 (2 H, d, J=8.4 Hz), 7.31 (2 H,m), 7.24 (1 H, s), 7.20 (2 H, d, J=8.4 Hz), 7.11 (1 H, m), 4.93 (1 H,s), 3.87 (1 H, m), 3.16 (1 H, m), 2.81 (1 H, dd, J=16.4, 7.8 Hz), 2.68(1 H, dd, J=16.4, 3.9 Hz), 2.57 (1 H, m), 2.12 (1 H, m), 2.00 (1 H, m),1.90-1.65 (6 H, m), 1.55-1.40 (2 H, m); MS (ESI) 446.0 [M−H]⁻.

Example 392-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2,2-dimethylcyclopentyl)methyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41 (2 H, d, J=8.2 Hz), 7.39 (1 H,m), 7.35-7.27 (3 H, m), 7.13 (2 H, d, J=8.2 Hz), 4.93 (1 H, s), 4.45 (1H, m), 3.20 (2 H, m), 3.00 (1 H, dd, J=16.8, 8.0 Hz), 2.51 (1 H, dd,J=16.8, 3.3 Hz), 2.10 (1 H, m), 1.90 (1 H, m), 1.65-1.35 (5 H, m), 0.88(3 H, s), 0.53 (3 H, s); MS (ESI) 474.1 [M−H]⁻.

Example 402-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclohexylmethyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.41 (2 H, d, J=8.6 Hz), 7.35-7.27(3 H, m), 7.18 (2 H, d, J=8.6 Hz), 7.14 (1 H, m), 4.95 (1 H, s), 3.08 (1H, m), 2.90 (1 H, dd, J=15.8, 9.2 Hz), 2.65 (1 H, m), 2.51 (1 H, dd,J=15.8, 2.7 Hz), 2.10 (1 H, m), 1.90-1.55 (4 H, m), 1.35-1.20 (8 H, m);MS (ESI) 460.4 [M−H]⁻.

Example 41

2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid

(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one(Example 35, Step B) was converted to the acid as described in Example1, Step H to give the title compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J=8.2 Hz), 7.23-7.19(1 H, m), 7.17-7.12 (1 H, t, J=7.4 Hz), 7.01 (1 H, s), 6.86 (2 H, d,J=8.2 Hz), 6.74 (1 H, d, J=7.4 Hz), 4.63 (1 H, d, J=10.2 Hz), 3.92 (1 H,dd, J=14.1, 6.3 Hz), 3.12-2.92 (3 H, m), 2.60 (1 H, dd, J=15.5, 3.3 Hz),2.34 (1 H, dd, J=14.1, 7.4 Hz), 2.29-2.08 (2 H, m), 0.95-0.85 (1 H, m),0.55-0.47 (1 H, m), 0.46-0.39 (1 H, m), 0.15-(−) 0.02 (2 H, m); MS (ESI)432.0 [M+H]⁺, 429.9 [M−H]⁻.

Example 422-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperidin-3-yl)aceticacid

Step A.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one

A 100 mL flame-dried round-bottomed flask equipped with a magnetic stirbar was charged with(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (1.32 g,4.12 mmol) (Example 1, Step E) and anhydrous THF (41.2 mL). Thissolution was cooled to 0° C. under argon and BuLi (3.30 mL, 8.24 mmol)was added. After 10 minutes allyl bromide (0.357 mL, 4.12 mmol) wasadded. After an additional 45 minutes the reaction was quenched by theaddition of sat. aq. NH₄Cl and the layers were separated. The aqueouslayer was extracted with EtOAc twice and the organics were pooled,washed with sat. aq. NaCl solution, dried (MgSO₄), filtered andconcentrated in vacuo to provide a colorless oil. Purification using aCombiflash Companion (flash column chromatography, Teledyne Isco,Lincoln, Nebr.) with a 120 g SiO₂ column and eluting with 10 to 100%EtOAc/hexanes provided the title compound.

¹H NMR (400 MHz, CDCl₃) δ ppm 2.07 (m, 1H), 2.15 (m, 1H), 2.45 (m, 1H),2.69 (m, 1H), 2.80 (m, 1H), 2.88 (m, 1H), 4.49 (d, J=10.3 Hz, 1H), 5.13(m, 2H), 5.82 (br s, 1H), 5.84 (m, 1H), 6.77 (m, 1H), 6.95 (d, J=8.4 Hz,2H), 7.01 (m, 1H), 7.12 (t, J=7.7 Hz, 1H), 7.18 (m, 1H), 7.21 (d, J=8.6Hz, 2H).

Step B.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-propylpiperidin-2-one

To a solution of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 42, Step A) (70 mg, 0.19 mmol) in 430 μL of DMF was addedsodium hydride (60% suspension in mineral oil, 20 mg, 0.51 mmol) at 0°C. The reaction was stirred at 0° C. for 15 min and then treated with1-bromopropane (53 μL, 0.58 mmol). After being stirred at 25° C. for 4h, the reaction was quenched with sat. aqueous NaHCO₃ and extracted(2×EtOAc). The combined organic layers were washed with sat. aq. NaCland NaHCO₃-solutions, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification of the residue bysilica gel prep plate (25% EtOAc/hexanes) provided the title compound asa colorless solid.

Step C.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-propylpiperidin-3-yl)aceticacid

The title compound was obtained from(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-propylpiperidin-2-one(Example 42, Step B) by a procedure similar to the one described inExample 1, Step H. Purification by silica gel prep plate (5% MeOH/DCM)provided the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.78 (t, J=7.34 Hz, 3 H) 1.33-1.45 (m, 1H) 1.45-1.57 (m, 1 H) 2.05-2.21 (m, 2 H) 2.48 (ddd, J=13.89, 9.39 and5.09 Hz, 1 H) 2.60 (dd, J=15.94 and 4.79 Hz, 1 H) 2.96 (dd, J=16.04 and7.43 Hz, 1H) 2.97-3.02 (m, 1 H) 3.02-3.12 (m, 1 H) 3.75 (ddd, J=13.69,9.68 and 6.36 Hz, 1 H) 4.41 (d, J=10.17 Hz, 1 H) 6.66-6.76 (m, 1 H) 6.87(d, J=8.41 Hz, 2 H) 6.97 (t, J=1.66 Hz, 1 H) 7.12 (t, J=7.83 Hz, 1 H)7.16-7.20 (m, 1 H) 7.23 (d, J=8.41 Hz, 2 H). MS (ESI) 420.2 [M+H]⁺.

Example 432-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)piperidin-2-one

To a solution of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 42, Step A) (70 mg, 0.19 mmol) in 430 μL of DMF was addedsodium hydride (60% suspension in mineral oil, 20 mg, 0.51 mmol) at 0°C. The reaction mixture was stirred at 0° C. for 15 min and aftertreatment with (bromomethyl)cyclobutane (66 μL, 0.58 mmol) the reactionmixture was heated to 70° C. for 15 h. The reaction mixture was cooledto room temperature, quenched with sat. aqueous NaHCO₃ and extracted(2×EtOAc). The combined organic layers were washed with sat. aq. NaCland NaHCO₃-solutions, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification of the residue bysilica gel prep plate (25% EtOAc/hexanes) provided the title compound asa colorless solid.

Step B.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)-2-oxopiperidin-3-yl)aceticacid

The title compounds were prepared from(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclobutylmethyl)piperidin-2-one(Example 43, Step A) as described in Example 1 Step H and purified byreversed phase HPLC on an Eclipse column (45-60% acetonitrile/water,gradient elution) to provide the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.52-1.69 (m, 2 H), 1.72-1.90 (m, 2 H),1.91-2.09 (m, 3 H), 2.14 (t, J=12.52 Hz, 1 H), 2.42 (dd, J=13.50 and7.43 Hz, 1 H), 2.46-2.57 (m, 1 H), 2.62 (dd, J=16.43 and 6.85 Hz, 1 H),2.86-3.01 (m, 2 H), 3.01-3.12 (m, 1 H), 4.05 (dd, J=13.50 and 7.24 Hz, 1H), 4.38 (d, J=9.98 Hz, 1 H), 6.70 (d, J=7.43 Hz, 1 H), 6.84 (d, J=8.22Hz, 2 H), 6.97 (s, 1 H), 7.12 (t, J=7.83 Hz, 1H), 7.16-7.20 (m, 1 H),7.22 (d, J=8.22 Hz, 2H). MS (ESI) 446.2 [M+H]⁺.

Example 442-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutylpiperidin-2-one

To a solution of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 42, Step A) (78 mg, 0.22 mmol) in 480 μL of DMF was addedpotassium tert-butoxide (40 mg, 0.54 mmol) at 0° C. The reaction mixturewas stirred at 0° C. for 15 min and then treated with1-bromo-2-methylpropane (82 μL, 0.76 mmol). After being stirred at 25°C. for 4 h, the reaction was quenched with sat. aqueous NaHCO₃ andextracted (2×EtOAc). The combined organic layers were washed with sat.aq. NaCl and NaHCO₃-solutions, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification of theresidue by silica gel prep plate (25% EtOAc/hexanes) provided the titlecompound as a colorless solid.

Step B.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isobutylpiperidin-2-one(Example 44, Step A) as described in Example 1, Step H to provide awhite solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.83 (d, J=6.65 Hz, 3 H), 0.85 (d, J=6.85Hz, 3 H), 1.93 (dq, J=8.39 and 6.66 Hz, 1 H), 2.06-2.16 (m, 2 H),2.17-2.24 (m, 1 H), 2.60 (dd, J=15.85 and 4.30 Hz, 1 H), 2.90-2.97 (m, 1H), 2.97-3.03 (m, 1 H), 3.04-3.13 (m, 1 H), 3.86 (dd, J=13.69 and 8.80Hz, 1 H), 4.41 (d, J=10.17 Hz, 1 H), 6.68-6.76 (m, 1 H), 6.84 (d, J=8.41Hz, 2 H), 6.96 (t, J=1.76 Hz, 1 H), 7.14 (t, J=7.82 Hz, 1 H), 7.18-7.22(m, 1 H), 7.24 (m, 2 H). MS (ESI) 434.2 [M+H]⁺.

Example 452-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)piperidin-2-one

The title compound was prepared from(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 42, Step A) and (bromomethyl)cyclopentane as described inExample 44, Step A. Purification of the residue by silica gel prep plate(25% EtOAc/hexanes) provided the title compound as a colorless solid.

Step B.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopentylmethyl)piperidin-2-one(Example 45, Step A) as described in Example 1, Step H to provide awhite solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 1.02-1.10 (m, 1 H), 1.12-1.19 (m, 1 H),1.46-1.57 (m, 2H), 1.59-1.71 (m, 4 H), 2.04-2.21 (m, 3 H), 2.32 (dd,J=13.69 and 6.85 Hz, 1 H), 2.60 (dd, J=15.77 and 4.03 Hz, 1 H),2.92-3.01 (m, 2H), 3.06 (dd, J=11.98 and 7.09 Hz, 1 H), 4.02 (dd,J=13.69 and 8.56 Hz, 1 H), 4.48 (d, J=10.03 Hz, 1 H), 6.72 (d, J=7.82Hz, 1 H), 6.84 (d, J=8.31 Hz, 2 H), 6.93-7.00 (m, 1 H), 7.14 (t, J=7.70Hz, 1 H), 7.18-7.22 (m, 1 H), 7.24 (m, 2H). MS (ESI) 460.2 [M+H]⁺.

Example 462-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid

Step A.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(pentan-3-yl)piperidin-2-one

To a solution of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 42, Step A) (440 mg, 1.221 mmol) in 3-bromopentane (3196 μL,25.6 mmol) under nitrogen at rt was added a dispersion of 60% sodiumhydride in mineral oil (244 mg, 6.11 mmol). Evolution of gas wasobserved. The reaction was stirred at room temperature for 10 min andthen heated to 120° C. under N₂ for 19 h. The reaction mixture wascooled to room temperature and quenched with sat. NH₄Cl. The layers wereseparated and the organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the titlecompound (375 mg, 71% yield) as a mixture of diastereomers.

Step B.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(pentan-3-yl)piperidin-2-one(Example 46, Step A) as described in Example 1 Step H. Purification byreversed phase preparatory HPLC (eluent: 0 to 100% MeCN+0.1% TFA inwater+0.1% TFA, over 20 minutes) provided the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J=7.53 Hz, 3 H) 0.94 (t,J=7.34 Hz, 3 H) 1.32-1.54 (m, 2 H) 1.85 (tt, J=14.38 and 7.24 Hz, 2 H)2.04-2.12 (m, 1 H) 2.18 (q, J=12.72 Hz, 1 H) 2.66 (dd, J=16.14 and 4.40Hz, 1 H) 2.85-3.01 (m, 2 H) 3.01-3.17 (m, 2 H) 4.33 (d, J=9.98 Hz, 1 H)6.71 (d, J=7.63 Hz, 1 H) 6.90-7.01 (m, 3 H) 7.09-7.22 (m, 2 H) 7.23-7.26(m, 1 H) 10.11 (br. s., 1 H). Mass spectrum (ESI) m/z=448 [M+H]⁺.

Example 47

Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate

To a suspension of 250 mg (0.578 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid (Example 35) in MeOH (3 mL) was added thionyl chloride (78.0 μl,1070 μmol) dropwise at 0° C. After being stirred at 25° C. for 14 h, thereaction was diluted (EtOAc), basified (sat NaHCO₃), extracted(2×EtOAc). The combined organic layers were washed with sat. aq. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure to provide the title compound as a colorlessliquid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.53-7.49 (1 H, m), 7.39 (2 H, d,J=8.6 Hz), 7.31-7.28 (2 H, m), 7.27-7.22 (3 H, m), 5.12 (1 H, s),4.25-4.18 (1H, m), 3.69 (3H, s), 3.20-3.14 (1 H, m), 2.85-2.82 (1 H, m),2.69-2.63 (1 H, m), 2.60-2.53 (1 H, m), 2.33-2.20 (2 H, m), 1.85-1.77 (1H, m), 1.20-1.15 (1 H, m), 0.70-0.63 (1 H, m), 0.61-0.53 (1 H, m),0.30-0.20 (2 H, m); MS (ESI) 445.9 [M+H]⁺.

Example 48

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamide

In a sealed tube, 60 mg (134 μmol) of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate(Example 47) and 4.8 mL of a solution of ammonia in methanol (7N, 3.4mmol) were stirred at 25° C. for 5 days. Then NaCN (3 mg) was added andthe resulting solution was stirred at 50° C. for 3 days. Excess NH₃ andMeOH were removed under reduced pressure. Separation by reversed phaseHPLC (10 to 90% AcCN/H₂O in 45 min) provided the title compound as a awhite solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52-7.45 (1 H, m), 7.37 (2 H, d,J=8.2 Hz), 7.33-7.29 (2 H, m), 7.26-7.22 (1 H, m), 7.17 (2 H, d, J=8.6Hz), 6.40 (1H, br. s.), 5.42 (1H, br. s.), 5.11 (1 H, br. s.), 4.21 (1H, dd, J=14.1, 6.3 Hz), 3.20-3.16 (1 H, m), 2.77-2.70 (1 H, m),2.60-2.48 (2 H, m), 2.33-2.25 (2 H, m), 1.92-1.85 (1 H, m), 1.22-1.15 (1H, m), 0.72-0.64 (1 H, m), 0.62-0.54 (1 H, m), 0.32-0.20 (2 H, m); MS(ESI) 430.9 [M+H]⁺.

Example 49

Ethyl2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetate

A solution of 40 mg (93 μmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid (Example 35) and ethyl 2-aminoacetate hydrochloride (14 mg, 102μmol) in DMF (0.31 mL) was treated at 0° C. withN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (27 mg, 139 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol(19 mg, 139 μmol), and sodium hydrogencarbonate (23 mg, 278 μmol),successively. After being stirred at 25° C. for 12 h, the reaction wasdiluted with water and extracted with EtOAc. The combined organic layerswere successively washed with 10% aq. citric acid solution, sat. aq.NaHCO₃ solution and sat. aq. NaCl solution, dried over Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure. Purificationof the residue by flash chromatography (SiO₂, 40% to 60% EtOAc/Hexanes,gradient elution) provided the title compound as a colorless film.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.47 (1 H, m), 7.35 (2 H, d,J=8.6 Hz), 7.32-7.28 (2 H, m), 7.26-7.24 (1 H, m), 7.16 (2 H, d, J=8.2Hz), 6.89 (1 H, br, s), 5.11 (1 H, s), 4.27-4.18 (3 H, m), 4.11-3.98 (2H, m), 3.20-3.15 (1 H, d, J=1.6 Hz), 2.83-2.72 (1 H, m), 2.63-2.55 (2 H,m), 2.32-2.16 (2 H, m), 1.95-1.87 (1 H, m), 1.29 (3 H, t, J=7.0 Hz),1.22-1.12 (1 H, m), 0.72-0.62 (1 H, m), 0.60-0.52 (1 H, m), 0.30-0.18 (2H, m); MS (ESI) 516.8 [M+H]⁺.

Example 50

2-(2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)aceticacid

To a solution of 38 mg (73 μmol) of ethyl2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamido)acetate(Example 49) in 0.75 mL of MeOH/THF/H₂O (2/2/1) was added a 2M solutionof lithium hydroxide in water (70 μl, 141 μmol) at 25° C. and themixture was stirred for 10 h. The reaction was acidified (1N aq. HCl)and extracted with DCM (2×). The combined organic layers weresuccessively washed with 10% aq. citric acid solution and sat. aq. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. Purification of the residue by reversed phaseHPLC (10 to 90% AcCN/H₂O with 0.1% TFA in 45 min) provided the titlecompound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.37-7.34 (1 H, m), 7.35 (2 H, d,J=8.2 Hz), 7.27-7.25 (1 H, m), 7.23-7.19 (1 H, m), 7.17-7.14 (1 H, m),7.08 (2 H, d, J=8.2 Hz), 5.00 (1 H, d, J=3.9 Hz), 4.18-4.08 (2 H, m),4.07-3.99 (1 H, m), 3.23-3.18 (1 H, m), 2.83-2.75 (2 H, m), 2.72-2.64 (1H, m), 2.35-2.23 (2 H, m), 2.05-1.95 (1 H, m), 1.16-1.05 (1 H, d, J=1.2Hz), 0.68-0.60 (1 H, m), 0.58-0.50 (1 H, m), 0.27-0.13 (2 H, m); MS(ESI) 488.8 [M+H]⁺, 486.9 [M−H]⁻.

Example 51

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide

To a solution of 120 mg (0.27 mmol) of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate(Example 47) in EtOH was added hydrazine, monohydrate (135 μl, 2688μmol). After being refluxed for 14 h, the reaction was concentrated,diluted (H₂O) and extracted (2×EtOAc). The combined organic layers werewashed with sat. aq. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification of theresidue by flash chromatography on silica gel (5% MeOH/CH₂Cl₂, gradientelution) provided the title compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.52-7.46 (1 H, m), 7.37 (2 H, d,J=8.6 Hz), 7.33-7.28 (2 H, m), 7.26-7.22 (1 H, m), 7.15 (2 H, d, J=8.6Hz), 5.10 (1 H, s), 4.20 (1 H, dd, J=14.1, 6.7 Hz), 3.20-3.15 (1 H, m),2.71-2.63 (1 H, m), 2.60-2.48 (2 H, m), 2.31-2.18 (1 H, m), 1.92-1.82 (1H, m), 1.20-1.10 (1 H, dt, J=7.9, 3.3 Hz), 0.70-0.63 (1 H, m), 0.59-0.52(1 H, m), 0.30-0.18 (2 H, m); MS (ESI) 445.9 [M+H]⁺.

Example 52

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)-N-hydroxyacetamide

A solution of 30 mg (0.07 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid (Example 35) in DMF (0.5 mL, c=0.14 M) was treated withN1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diaminehydrochloride (0.03 g, 0.1 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol(0.02 g, 0.1 mmol), hydroxylamine hydrochloride (0.006 ml, 0.1 mmol) andsodium hydrogencarbonate (0.02 g, 0.2 mmol) successively. After beingstirred at 25° C. for 12 h, the reaction was diluted with water andextracted with EtOAc. The combined organic layers were successivelywashed with sat. aq. NaHCO₃ solution and sat. aq. NaCl solution, driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by reversed phase HPLC (10 to 90%AcCN/H₂O with 0.1% TFA in 45 min) to give the title compound as a whitesolid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.45 (1 H, s), 7.41-7.16 (5 H, m),7.16-6.98 (2 H, m), 5.10 (1 H, br. s.), 4.26-4.13 (1 H, m), 3.25-3.17 (1H, m), 2.65 (3 H, br. s.), 2.30 (2H, dd, J=14.1, 7.8 Hz), 1.91 (1 H, br.s.), 1.15 (1 H, d, J=2.0 Hz), 0.77-0.65 (1 H, m), 0.65-0.51 (1 H, m),0.37-0.14 (2 H, m).

Example 53

(S)-Ethyl2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-(methylsulfonamido)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate

Methanesulfonamide (0.02 g, 0.2 mmol), N-ethyl-N-isopropylpropan-2-amine(0.05 ml, 0.3 mmol), di(1H-imidazol-1-yl)methanone (0.04 g, 0.2 mmol)and2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid (Example 3, 0.030 g, 0.06 mmol) were combined in 2 mL of THF. Afterbeing stirred at 25° C. for 12 h, sat. NH₄Cl solution was added and thereaction mixture was extracted with EtOAc. The combined organic layerswere successively washed with sat. aq. NaHCO₃ solution and sat. aq. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. The residue was purified by reversed phase HPLC(10 to 90% AcCN/H₂O with 0.1% TFA in 45 min) to give the title compoundas a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.45-7.33 (3 H, m), 7.33-7.21 (5 H,m), 4.88 (1 H, d, J=3.9 Hz), 4.27-4.10 (2 H, m), 3.48 (1 H, dd, J=8.8,3.3 Hz), 3.30 (3 H, s), 3.20 (1 H, dd, J=4.7, 0.8 Hz), 3.04-2.74 (2 H,m), 2.72-2.59 (1 H, m), 2.48-2.28 (2 H, m), 2.03 (1 H, s), 1.63-1.46 (1H, m), 1.28 (3 H, t, J=7.2 Hz), 0.69 (3 H, t, J=7.4 Hz).

Example 54

(S)-Ethyl2-((2S,3R,5R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-(2-((3-morpholinopropyl)amino)-2-oxoethyl)-6-oxopiperidin-1-yl)butanoate

The title compound was prepared as described in Example 49, using2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid (Example 3) as starting material.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.34 (2 H, d, J=8.6 Hz), 7.30-7.16(5 H, m), 7.11-7.03 (1 H, m), 4.73 (1 H, d, J=5.5 Hz), 4.14 (2 H, q,J=7.3 Hz), 4.09-3.92 (4 H, m), 3.67-3.51 (2 H, m), 3.50-3.40 (1 H, m),3.39-3.30 (2 H, m), 3.25 (1 H, dd, J=8.8, 3.3 Hz), 3.22-3.12 (2 H, m),2.98-2.50 (5 H, m), 2.33-2.03 (5 H, m), 1.52-1.37 (0 H, m), 1.26 (3 H,t, J=7.2 Hz), 0.60 (3H, t, J=7.4 Hz).

Example 55

(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-oneStep A.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetonitrile

A solution of 136 mg (0.315 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamide(Example 48) and triethylamine (220 μl, 1576 μmol) in 5 mL of THF wastreated with trifluoroacetic anhydride (111 μl, 788 μmol) at 0° C. Afterbeing stirred at 0° C. for 2 h, the reaction was quenched (sat. NH₄Cl),extracted (2×EtOAc) and washed (sat. aq. NaCl solution). The combinedorganic layer were dried (Na₂SO₄) and concentrated under the reducedpressure.

After being stirred at 0° C. for 2 h, sat. NH₄Cl solution was added andthe reaction mixture was extracted with EtOAc. The combined organiclayers were washed with sat. aq. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification of the residue by flash chromatography (SiO₂, 20-25%EtOAc/Hexanes) provided the title compound which was used withoutfurther purification.

Step B.(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

To a solution of 136 mg (0.33 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetonitrile(Example 55, Step A) in 1.8 mL of DMF was added ammonium chloride (176mg, 3290 μmol) and sodium azide (214 mg, 3290 μmol). The resultingmixture was stirred at 90° C. for 4 days. Then, the reaction wasacidified (aq. 10% citric acid) and extracted (2×EtOAc). The combinedorganic layers were washed with sat. aq. NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. Separation by reversed phase HPLC (60-90% AcCN/H₂O in 30 min)provided the title compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.51-7.48 (1 H, s), 7.35 (2 H, d,J=8.2 Hz), 7.32-7.28 (2 H, m), 7.25-7.21 (1 H, m), 6.86 (2 H, d, J=8.2Hz), 5.14 (1 H, s), 4.23 (1 H, dd, J=14.1, 6.7 Hz), 3.40 (1 H, dd,J=15.3, 3.1 Hz), 3.28-3.20 (1 H, m), 3.15 (1 H, dd, J=15.1, 8.0 Hz),2.60-2.52 (1 H, m), 2.33 (1 H, dd, J=14.1, 8.2 Hz), 2.26-2.18 (2 H, br.s.), 2.04-1.93 (1 H, m), 1.25-1.15 (1 H, m), 0.77-0.70 (1 H, m),0.68-0.59 (1 H, m), 0.36-0.24 (2 H, m); MS (ESI) 456.0 [M+H]⁺, 453.9[M−H]⁻.

Example 56

(3R,5R,6S)-3-((1,3,4-oxadiazol-2-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

To a solution of 20 mg (45 μmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide(Example 51) in 0.2 mL of toluene was added ethyl formimidatehydrochloride (6.4 mg, 58 μmol). The reaction mixture was heated toreflux for 14 h and then the reaction was concentrated under reducedpressure. Separation by reversed phase HPLC (10 to 90% AcCN/H₂O in 40min) provided the title compound as a colorless film.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.35 (1 H, s), 7.50-7.45 (1 H, m),7.37 (2 H, d, J=8.6 Hz), 7.34-7.28 (2 H, m), 7.26-7.22 (1 H, m), 7.13 (2H, d, J=8.6 Hz), 5.13 (1 H, s), 4.22-4.17 (1 H, m), 3.38-3.35 (2 H, m),3.24-3.18 (1 H, m), 2.80-2.72 (1 H, m), 2.35-2.28 (1 H, m), 2.25-2.18 (1H, m), 1.96-1.86 (1 H, m), 1.21-1.12 (1 H, m), 0.70-0.62 (1 H, m),0.61-0.54 (1 H, m), 0.30-0.20 (2 H, m); MS (ESI) 456.0 [M+H]⁺.

Example 57

(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)piperidin-2-one

To a solution of 40 mg (90 μmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetohydrazide(Example 51) in 0.2 mL of toluene was added methyl acetimidatehydrochloride (13 mg, 116 μmol). The reaction mixture was heated toreflux for 14 h and then the reaction was concentrated under reducedpressure. Separation by reversed phase HPLC (10 to 90% AcCN/H₂O in 45min) provided the title compound as a colorless film.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.47-7.45 (1 H, s), 7.38 (2 H, d,J=8.6 Hz), 7.33-7.29 (2 H, m), 7.24-7.19 (1 H, m), 7.15 (2 H, d, J=8.6Hz), 5.12-5.10 (1 H, m), 4.18 (1 H, dd, J=14.1, 6.7 Hz), 3.38-3.23 (2 H,m), 3.22-3.18 (1 H, m), 2.80-2.72 (1 H, m), 2.54 (3 H, s), 2.36-2.22 (2H, m), 1.94-1.88 (1 H, m), 1.20-1.10 (1 H, m), 0.70-0.63 (1 H, m),0.60-0.52 (1 H, m), 0.30-0.20 (2 H, m); MS (ESI) 469.9 [M+H]⁺.

Example 58

2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide

To a solution of2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid (Example 41) (83 mg, 0.192 mmol), methanesulfonamide (22.59 mg,0.230 mmol) and 4-dimethylaminopyridine (1.057 mg, 0.00865 mmol) in DCM(2 mL) was added diisopropylethylamine (80 μL, 0.461 mmol). The reactionmixture was stirred at room temperature for one minute before addingbromo-tris-pyrrolidino-phosphonium hexafluorophosphate (125 mg, 0.269mmol). The reaction mixture was stirred at room temperature for 3 hours.The reaction was quenched with 1N HCl and the aqueuos layer wasextracted with DCM (10 mL). The combined organic layers were washed with1N HCl, 1N NaOH, sat. aq. NaCl solution and concentrated under reducedpressure. The residue was purified by reversed phase preparatory HPLC(column: Gemini-NX C₁₈ 5 μm column; Phenomonex, Torrance, Calif.;eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) toafford the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.06-0.04 (m, 1 H) 0.06-0.16 (m, 1H) 0.43 (dd, J=8.51 and 4.60 Hz, 1 H) 0.47-0.60 (m, 1 H) 0.88 (d, J=6.26Hz, 1 H) 2.09-2.18 (m, 1 H) 2.29 (dt, J=14.04 and 6.77 Hz, 2 H) 2.62(dd, J=15.26 and 3.52 Hz, 1 H) 2.90 (dd, J=15.26 and 7.63 Hz, 1 H) 3.02(t, J=2.64 Hz, 1 H) 3.14 (d, J=3.72 Hz, 1 H) 3.32 (s, 3 H) 3.93 (dd,J=14.28 and 6.26 Hz, 2 H) 4.64 (d, J=10.17 Hz, 1 H) 6.74 (d, J=7.63 Hz,1 H) 6.85-6.91 (m, 2 H) 7.00 (d, J=1.76 Hz, 1 H) 7.10-7.26 (m, 4 H).Mass Spectrum (ESI) m/z=509 [M+H]⁺.

Example 592-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamide

Step A. Methyl2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate

To a solution of2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid (Example 41) (500 mg, 1.156 mmol) in 10% MeOH in DCM (10 mL) wasadded (trimethylsilyl)diazomethane (2.0 M in diethyl ether) (1 mL). Theyellow colored reaction mixture was stirred at room temperature for 30min. The reaction was concentrated under reduced pressure and waspurified by flash chromatography on silica gel (eluent: 0 to 50% EtOAcin hexanes) to give the title compound as a clear oil.

Step B.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetamide

A sealed tube was charged with methyl2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)acetate(Example 59, Step A) (109 mg, 0.244 mmol), ammonia, 7N solution inmethanol (2 ml, 14.00 mmol) and sodium cyanide (1.197 mg, 0.024 mmol).The tube was sealed and heated to 50° C. The pressure reached 35kilopascals after 1 hour. The reaction was stirred at 50° C. for 18 h.The reaction was cooled to rt and anhydrous ammonia (gas) was bubbledthrough the solution for ten minutes at room temperature. The reactionmixture was capped and heated to 50° C. for 18 h. The reaction wascooled to rt and anhydrous ammonia (gas) was bubbled through thesolution for twenty minutes at room temperature. The reaction mixturewas capped and heated to 50° C. for 2 days. The crude reaction wasconcentrated under reduced pressure and purified by reversed phasepreparatory HPLC (column: Gemini-NX C₁₈ 5 um column; Phenomonex,Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA,over 20 minutes) to afford the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.05-0.04 (m, 1 H) 0.06-0.15 (m, 1H) 0.36-0.45 (m, 1 H) 0.46-0.56 (m, 1 H) 0.79-0.93 (m, 1 H) 2.11-2.20(m, 1 H) 2.29 (dt, J=13.99, 6.90 Hz, 1 H) 2.64-2.73 (m, 1 H) 2.75-2.83(m, 1 H) 2.96-3.13 (m, 2 H) 3.91 (dd, J=14.09, 6.46 Hz, 1 H) 4.63 (d,J=9.98 Hz, 1 H) 6.41 (br. s., 1 H) 6.75 (dt, J=7.58, 1.59 Hz, 2 H)6.83-6.90 (m, 2 H) 7.01 (t, J=1.96 Hz, 1 H) 7.10-7.26 (m, 4 H). MassSpectrum (ESI) m/z=431 [M+H]⁺.

Example 60(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

Step A.(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one

A 100 mL round-bottomed flask was placed under vacuum and heated with aheat gun to ensure dryness. The flask was allowed to cool to roomtemperature and a solution of 500 mg (1.56 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1,Step E) in THF (12 mL) under argon was added and cooled to 0° C.Butyllithium (1.6M in hexanes, 2440 μL, 3.90 mmol) was added followed by5-chloromethyl-1H-tetrazole (185 mg, 1.561 mmol) and the reactionmixture was stirred for 15 minutes at 0° C. The reaction was quenchedwith saturated ammonium chloride solution and extracted with ethylacetate. The aqueous layer was acidified with 1M HCl. The aqueous layerwas extracted with ethyl acetate (2×30 mL) and the combined organiclayers were washed with sat. aq. NaCl solution, dried over sodiumsulfate, and concentrated under reduced pressure. The residue waspurified by reversed phase preparatory HPLC (column: Gemini-NX C₁₈ 5 μmcolumn; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA inwater+0.1% TFA, over 25 minutes) to afford the title compound.

Step B.(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

A solution of(3S,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 60, Step A) (65 mg, 0.162 mmol) in DMF (1.6 mL) was cooled to0° C. and sodium tert-butoxide (31.1 mg, 0.323 mmol) was added. Thereaction mixture was stirred at 0° C. for ten minutes before adding(bromomethyl)cyclopropane (78 μL, 0.808 mmol). The reaction mixture waswarmed to room temperature and stirred for 16 hours, quenched withsaturated ammonium chloride and diluted with water and ethyl acetate.The aqueous layer was extracted with ethyl acetate and the organiclayers were combined, washed with 1M LiCl, sat. aq. NaCl solution, driedover sodium sulfate, and concentrated under reduced pressure. Theresidue was purified by reversed phase preparatory HPLC (column:

-   Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.; eluent: 0    to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to afford    the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.08-0.02 (m, 1 H) 0.11 (dt,J=9.44 and 4.77 Hz, 1 H) 0.38-0.46 (m, 1 H) 0.50 (td, J=8.31 and 4.50Hz, 1 H) 0.78-0.89 (m, 1 H) 2.18-2.28 (m, 2 H) 2.31-2.41 (m, 1 H)2.96-3.07 (m, 2 H) 3.29 (dd, J=14.87 and 7.82 Hz, 1 H) 3.47-3.56 (m, 1H) 3.89 (dd, J=14.09 and 6.46 Hz, 1 H) 4.58 (d, J=9.98 Hz, 1 H)6.71-6.76 (m, 1 H) 6.80-6.87 (m, 2 H) 6.98 (d, J=1.76 Hz, 1 H) 7.12-7.18(m, 1 H) 7.19-7.25 (m, 3 H). Mass Spectrum (ESI) m/z=456 [M+H]⁺.

Example 61(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-((5-methylisoxazol-3-yl)methyl)piperidin-2-one

The title compound was prepared from(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1,Step E),3-(bromomethyl)-5-methylisoxazole, and (bromomethyl)cylopropaneas described in Example 60.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.05-0.04 (m, 1 H) 0.05-0.14 (m, 1H) 0.32-0.41 (m, 1 H) 0.42-0.51 (m, 1 H) 0.79-0.94 (m, 1 H) 2.04-2.09(m, 2 H) 2.28 (dd, J=14.28 and 7.24 Hz, 1 H) 2.37 (d, J=0.59 Hz, 3 H)2.86-3.04 (m, 3 H) 3.33-3.41 (m, 1 H) 3.93 (dd, J=14.18 and 6.55 Hz, 1H) 4.56 (d, J=9.98 Hz, 1 H) 5.92 (d, J=0.78 Hz, 1 H) 6.70 (dt, J=7.58and 1.30 Hz, 1 H) 6.80-6.86 (m, 2 H) 6.95 (t, J=1.76 Hz, 1 H) 7.06-7.11(m, 1 H) 7.13-7.17 (m, 1 H) 7.17-7.23 (m, 2 H). Mass Spectrum (ESI)m/z=469 [M+H]⁺.

Example 62 (rac)2-((2′S,3′R,5′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)aceticacid

Step A. 1-(3-chlorophenyl)pent-4-en-1-one

To a solution of 3-chlorobenzoyl chloride (7 ml, 54.7 mmol) in THF (60mL) was added copper (I) iodide (0.521 g, 2.73 mmol). The slurry wascooled to −10° C. and 3-butenylmagnesium bromide (0.5M in THF) (112 ml,55.8 mmol) was added dropwise via cannula over 30 min. The reactionmixture was stirred at −10° C. for 1 h and then warmed to roomtemperature. The reaction mixture was concentrated to 25 mL and dilutedwith 100 mL DCM and 100 mL 1M HCl. The layers were separated and theorganic layer was filtered. The filtrate was washed with sat. NaHCO₃,dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (eluent: 0 to 50% DCMin hexanes) to give the title compound.

Step B. 6-chloro-3-(1-(3-chlorophenyl)pent-4-enylidene)indolin-2-one

To a mixture of 1-(3-chlorophenyl)pent-4-en-1-one (Example 62, Step A)(14.86 g, 76 mmol) and 6-chloroindolin-2-one (12.79 g, 76 mmol) intoluene (50 mL) at room temperature was added pyrrolidine (6.31 mL, 76mmol). The slurry was heated at reflux with a Dean Stark trap for 6 h.The reaction mixture was cooled to room temperature and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (eluent: 10 to 20% EtOAc in hexanes) to give the titlecompound.

Step C. 6-chloro-3-(1-(3-chlorophenyl)pent-4-enyl)indolin-2-one

To a yellow slurry of6-chloro-3-(1-(3-chlorophenyl)pent-4-enylidene)indolin-2-one (Example62, Step B) (12.81 g, 37.2 mmol) in MeOH (200 mL) at room temperaturewas slowly added sodium borohydride (1.689 g, 44.7 mmol). Evolution ofgas was observed. The yellow reaction mixture was stirred at roomtemperature for 30 min. Additional sodium borohydride (1.689 g, 44.7mmol) was slowly added and the reaction mixture was stirred at roomtemperature for 1 h. The reaction mixture was poured into water (200mL). A precipitate formed and the mixture was sonicated for 15 min thenfiltered. The filtrate was concentrated under reduced pressure to 36 mLand then extracted with EtOAc twice. The organic layers were combined,dried over Na₂SO₄ and concentrated under reduced pressure to provide thetitle compound.

Step D. 3-bromo-6-chloro-3-(1-(3-chlorophenyl)pent-4-enyl)indolin-2-one

To a solution of 6-chloro-3-(1-(3-chlorophenyl)pent-4-enyl)indolin-2-one(Example 62, Step C (13.0 g, 37.5 mmol) in THF (200 mL) (previouslydegassed with Ar) at −78° C. under Ar was addedN1,N1,N2,N2-tetramethylethane-1,2-diamine (11.79 mL, 79 mmol)(previously degassed with Ar) and butyllithium (1.6 M in hexanes) (49.3mL, 79 mmol) (previously degassed with Ar) via addition funnel. Thelight brown reaction mixture was stirred at −78° C. for 30 min., wrappedin foil and recrystallized 1-bromopyrrolidine-2,5-dione (6.68 g, 37.5mmol) in THF (50 mL) (previously degassed with Ar) was added viacannula. After the addition the reaction was quenched immediately withsat. potassium phosphate mono basic and warmed to room temperature. Themixture was extracted with EtOAc twice. The organic layers werecombined, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (eluent: 0 to10% EtOAc in hexanes) to give the title compound as a 1:1.7 ratio ofdiastereomers.

Step E.4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoic acid

To a rapidly stirred solution of3-bromo-6-chloro-3-(1-(3-chlorophenyl)pent-4-enyl)indolin-2-one (Example62, Step D) (7.74 g, 18.21 mmol) in H₂O/CCl₄/MeCN (1.5/1/1) (80 mL/50mL/50 mL) was added sodium periodate (15.58 g, 72.8 mmol) andruthenium(III) chloride hydrate (0.205 g, 0.910 mmol). The reactionmixture was stirred vigorously for 30 min and the reaction monitored byTLC. The reaction mixture was acidified (10% citric acid) and extractedwith EtOAc. The organic layer was washed with sat. aq. NaCl solution,dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (eluent: 30 to 70%EtOAc in hexanes) to give the title compound.

Step F. methyl4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoate

To a solution of4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoic acid(Example 62, Step E) (5.38 g, 12.14 mmol) in MeOH (120 mL) at roomtemperature was added one drop of concentrated sulfuric acid. Thereaction mixture was stirred at room temperature for 18 h and thenconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (eluent: 0 to 50% EtOAc in hexanes) to givethe title compound.

Step G. (rac) (S)-methyl4-((S)-6-chloro-3-(cyclopropylmethylamino)-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoateand (rac) (R)-methyl4-((S)-6-chloro-3-(cyclopropylmethylamino)-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoate

A solution of methyl4-(3-bromo-6-chloro-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoate(Example 62, Step F) (110 mg, 0.241 mmol) in DCE (4 mL) was heated atreflux. Cesium carbonate (157 mg, 0.481 mmol) and cyclopropylmethylaminehydrochloride (25.9 mg, 0.241 mmol) in DCE (1 mL) were added in oneportion. The reaction mixture was heated at reflux for 5 h and thencooled to room temperature. The reaction mixture was filtered throughcelite and washed with DCM. The filtrate was concentrated and thediastereomeric pairs were separated by flash chromatography on silicagel (eluent: 20 to 60% EtOAc in hexanes) to give the title compounds.The more polar isomer is used in Example 62, Step H.

Step H. (rac)(2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)spiro[indoline-3,2′-piperidine]-2,6′-dione

A solution of (rac) (R)-methyl4-((S)-6-chloro-3-(cyclopropylmethylamino)-2-oxoindolin-3-yl)-4-(3-chlorophenyl)butanoate(Example 62, Step G, more polar isomer) in DCM was washed with satNaHCO₃, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was dissolved in distilled xylene (5 mL) and the reactionmixture was heated to 135° C. for 24 h. The reaction mixture was cooledto room temperature and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (eluent: 20 to 60%EtOAc in hexanes) to give the title compound.

Step I. (rac)(2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione

To a solution of (rac)(2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)spiro[indoline-3,2′-piperidine]-2,6′-dione(Example 62, Step H) (114 mg, 0.274 mmol) in DMF (2 mL) at 0° C. wasadded a dispersion of 60% sodium hydride in mineral oil (10.98 mg, 0.274mmol) followed by (2-(chloromethoxy)ethyl)trimethylsilane (48.4 μL,0.274 mmol). The reaction mixture was stirred at 0° C. for 30 min andthen warmed to room temperature and stirred at room temperature for 24h. The reaction mixture was poured into ice water and extracted withEtOAc. The organic layer was washed with 1M LiCl, sat. aq. NaClsolution, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (eluent: 0 to50% EtOAc in hexanes) to give the title compound.

Step J. (rac)(2′S,3′R,5′S)-5′-allyl-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione

To a solution of (rac)(2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1′-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62,Step I) (97 mg, 0.178 mmol) in THF (1 mL) at −78° C. under Ar was addedfreshly prepared LDA (1.0 M in THF) (178 μL, 0.178 mmol). The reactioncolor turned yellowish orange. The reaction was stirred at −78° C. for30 min then distilled allyl bromide (15.39 μL, 0.178 mmol) was added.The reaction was stirred at −78° C. for 10 min then warmed to 0° C. Thereaction was quenched with sat. NH₄Cl and warmed to room temperature.The mixture was diluted with EtOAc and the layers were separated. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel(eluent: 0 to 25% EtOAc in hexanes) to give the title compound.

Step K. (rac)2-((2′S,3′R,5′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-5′-yl)aceticacid

To a rapidly stirred solution of (rac)(2′S,3′R,5′S)-5′-allyl-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62, Step J) (46 mg, 0.079mmol) in H₂O/CCl₄/MeCN (0.75 ml/0.5 mL/0.5 mL) was added sodiumperiodate (67.2 mg, 0.314 mmol) and ruthenium(III) chloride hydrate(1.771 mg, 7.85 μmol). The reaction mixture was stirred vigorously for19 h and then acidified (10% citric acid) and filtered through a plug ofcelite and washed with EtOAc. The filtrate was transferred to aseparatory funnel and extracted with EtOAc. The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure to provide the titlecompound.

Step L. (rac)2-((2′S,3′R,5′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-(hydroxymethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)aceticacid

To a solution of (rac)2-((2′S,3′R,S′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxo-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-5′-yl)aceticacid (Example 62, Step K) (47 mg, 0.078 mmol) in DCM (0.8 mL) at roomtemperature was added 0.2 mL TFA. The reaction mixture was stirred atroom temperature for 19 h before concentrating under reduced pressure.The residue was purified by flash chromatography on silica gel (eluent:50 to 100% EtOAc in hexanes) to give the title compound.

Step M. (rac)2-((2′S,3′R,S′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)aceticacid

To a solution of (rac)2-((2′S,3′R,S′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-(hydroxymethyl)-2,6′-dioxospiro[indoline-3,2′-piperidine]-5′-yl)aceticacid (Example 62, Step L) (12.6 mg, 0.025 mmol) in MeOH (1 mL) at roomtemperature was added DIEA (8.74 μL, 0.050 mmol). The reaction mixturewas stirred at room temperature for 1 h. The reaction was quenched with10% citric acid and concentrated under reduced pressure. The residue waspurified by reversed phase preparatory HPLC (column: Gemini-NX C₁₈ 5 umcolumn; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA inwater+0.1% TFA) to give the title compound.

¹H NMR (400 MHz, ACETONITRILE-d₃) δ ppm −0.25-−0.18 (1 H, m) −0.12-−0.04(1 H, m) 0.20-0.34 (2 H, m) 0.66-0.77 (1 H, m) 1.64-1.73 (1 H, m) 2.68(1 H, dd, J=14.3 and 7.0 Hz) 2.73-2.81 (1 H, m) 2.86-3.02 (1 H, m)3.12-3.33 (3 H, m) 3.53-3.65 (1 H, m) 6.61 (1 H, d, J=1.8 Hz) 6.79-6.91(2 H, m) 7.08 (1 H, t, J=7.8 Hz) 7.11-7.20 (2 H, m) 7.49 (1 H, d, J=8.2Hz) 8.29 (1 H, br s). Mass Spectrum (ESI) m/z=473 [M+H]⁺.

Example 63

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid Step A. 2-(3-Chlorophenyl)-1-(5-chlorothiophen-2-yl)ethanone

To a 500-mL round-bottomed flask was added silica gel 60 (21 g, 350mmol) and the flask was heated with a heat gun under high vacuum for 30min. The system was cooled to room temperature and phosphorus pentoxide(8.75 mL, 148 mmol) was added. The mixture was stirred at 110° C. (oilbath) under high vacuum for 120 min. The mixture was allowed to cool toroom temperature. 3-chlorophenylacetic acid (15.6 g, 91 mmol),2-chlorothiophene (33.8 mL, 366 mmol) and DCE (50 mL) were added. Thereaction mixture was stirred at reflux for 4 hours. LCMS analysis showedthe reaction was complete. The reaction mixture was allowed to cool toroom temperature. The reaction mixture was diluted with ether (300 mL)and filtered. The organic solution was concentrated under reducedpressure. The residue was triturated with hexane to afford the titlecompound as an off-white solid. The hexane mother liquid wasconcentrated and purified by flash chromatography (SiO₂, 0 to 30%EtOAc/Hex, a gradient elution) provided another batch of the titlecompound as a light yellow solid. Mass Spectrum (ESI) m/z=271 (M+1).

Step B. rac. Methyl4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)-5-oxopentanoate

To a solution of 7.35 g (27.1 mmol) of2-(3-chlorophenyl)-1-(5-chlorothiophen-2-yl)ethanone (Example 63, StepA) and acrylic acid methyl ester (2.81 mL, 31.2 mmol) in DCM (60 mL) wasadded 1,8-diazabicyclo[5.4.0]undec-7-ene (4.05 mL, 27.1 mmol) in DCM (10mL) slowly at 0° C. over 20 min. Then the reaction was allowed to warmto ambient temperature. After being stirred at 25° C. for two days, thereaction mixture was diluted with DCM and washed with 2N HCl, water andsat. aq. NaCl solution. The organic extract was dried over Na₂SO₄. Thesolution was filtered and concentrated in vacuo to give the crudematerial as light yellow oil. The crude material was absorbed onto aplug of silica gel and purified by chromatography through a pre-packedsilica gel column (220 g), eluting with a gradient of 0% to 30% EtOAc inhexane, to provided the title compound as a light-yellow oil. MassSpectrum (ESI) m/z=357 (M+1).

Step C. rac (4S,5S)(4R,5R)methyl4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)-5-hydroxypentanoate

To a solution of 8.20 g (22.95 mmol) of methyl4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)-5-oxopentanoate (Example63, Step B) in MeOH (100 mL) was added sodium borohydrate (0.809 mL,22.95 mmol) portion-wise at 0° C. Then the reaction was stirred at 0° C.for 30 min. LCMS analysis showed the reaction went to completion.Ice-water was added to quench the reaction. The reaction mixture wasconcentrated under reduced pressure to remove most of MeOH. The residuewas extracted with DCM (3×100 mL). The combined organic layers werewashed with sat. aq. NaCl solution, dried over Na₂SO₄, and concentratedunder reduced pressure. Purification of the residue by flashchromatography (TLC, SiO₂, 20 to 30% EtOAc/hexanes, gradient elution)provided the title compound as a colorless oil.

Step D. rac.(4S,5R)(4R,5S)-methyl-5-azido-4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)pentanoate

To a solution of 1.18 g (3.28 mmol) of racemic (4S,5S)(4R,5R)-methyl4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)-5-hydroxypentanoate(Example 63, Step C) in toluene (10 mL) was added1,8-diazabicyclo[5.4.0]undec-7-ene (0.639 mL, 4.27 mmol) over 5 min at0° C. with stirring. To the above solution, diphenylphosphoryl azide(0.852 mL, 3.94 mmol) was added dropwise over a period of 8 min. Thereaction mixture was stirred at 0° C. to rt for 14 hours and monitoredby LCMS analysis. The reaction mixture was diluted (sat. aq. NH₄Cl),extracted (3×EtOAc), and washed (2×sat. aq. NaCl solution). The combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure. The crude material was dissolved in small amount of DCM forchromatography. The insoluble material was removed by filtration and thesolution was absorbed onto a plug of silica gel and purified bychromatography through a Redi-Sep pre-packed silica gel column (40 g),eluting with a gradient of 0% to 60% EtOAc in hexane, to provide theracemic title compound as a colorless oil.

Mass Spectrum (ESI) m/z=406 (M+23).

Step E.(5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-one

To a solution of 7.8 g (20.3 mmol) of racemic (4S,5R)(4R,5S)-methyl5-azido-4-(3-chlorophenyl)-5-(5-chlorothiophen-2-yl)pentanoate (Example63, Step D) in THF/H₂O (4/1, 75 mL) was added trimethylphosphine, 1.0Msolution in tetrahydrofuran (24.36 mL, 24.36 mmol). After being stirredfor 1 h at 23° C., LCMS analysis showed reaction was complete. Most ofTHF was removed under reduced pressure and the residue was basified(ice-cold 2 M LiOH) and the product was extracted (3×DCM) and washed(2×sat. aq. NaCl solution). The combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure to provide a crudemixture of amines as a yellow solid.

The crude amine from above was dissolved in MeOH/saturated aq. NaHCO₃(4/1, 60 mL, c=0.04 M) and the reaction was refluxed for 3 h. After LCMSanalysis showed the reaction to be complete, excess solvent was removedunder reduced pressure, the residue was diluted (water), extracted(2×10% MeOH/DCM), and washed (1×sat. aq. NaCl solution). The combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure to provide the crude title compound.

The crude material was absorbed onto a plug of silica gel and purifiedby chromatography through a pre-packed silica gel column (220 g),eluting with a gradient of 20% to 100% EtOAc in CH₂Cl₂, to provide theracemic title compound as a white solid.

Individual enantiomers of the racemic(5R,6S)(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-onewere separated by chiral SFC on a 250×30 mm Chiralcel AS-H column with50 g/min MeOH(+20 mM NH₃)+50 g/min CO₂ on Thar 350 SFC (TharTechnologies, Inc., Pittsburgh, Pa.). Outlet pressure=100 bar; Temp.=46°C.; Wavelength=245 nm. Run time=20 min.; cycle time=17 min. The titlecompound(5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-one wasobtained as the faster eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.24 (2 H, m), 7.10 (1 H, m),6.93-6.95 (1 H, m) 6.23 (1 H, d, J=4Hz), 6.42 (1 H, d, J=4 Hz), 6.09 (1H, s), 4.73 (1 H, d, J=8 Hz), 2.87-2.94 (1 H, m), 2.60-2.65 (2 H, m),2.05-2.25 (2 H, m); Mass Spectrum (ESI) m/z=326 (M+1); [α]_(D)=+165.8(T=24.7° C., c=0.104, CHCl₃)

Also obtained by the above method was the enantiomer of the titlecompound,(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-one asthe slower eluting isomer.

[α]_(D)=−158 (T=24.8° C., c=0.104, CHCl₃)

Step F. rac.(5R,6S)(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)piperidin-2-one

The title compound was prepared from racemic (5R,6S),(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)piperidin-2-one(Example 63, Step E) as described in Example 35, Step A.

¹H NMR (400 MHz, CHLOROFORM-d) α ppm 7.34 (1H, br s), 7.25-7.30 (2 H,m), 7.13-7.17 (1 H, m), 6.74 (1 H, d, J=4 Hz), 6.56 (1 H, d, J=4 Hz),5.06 (1 H, d, J=4 Hz), 4.13-4.19 (1 H, m), 3.19-3.23 (1 H, m), 2.46-2.60(3H, m), 2.23-2.29 (1 H, m), 2.01-2.10 (1 H, m), 1.05-1.13 (1 H, m),0.59-0.66 (1 H, m), 0.49-0.56 (1 H, m), 0.27-0.33 (1 H, m), 0.18-0.24 (1H, m). Mass Spectrum (ESI) m/z=380 (M+1).

Step G. (3R,5R,6S)(3S,5S,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-oneand (3S,5R,6S)(3R,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one

The title compounds were prepared from racemic((5R,6S)(5S,6R)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)piperidin-2-one(Example 63, Step F) as described in Example 1, Step G and were obtainedas a mixture of stereoisomers. The individual racemic stereoisomers wereseparated by silica gel chromatography.

The title compound (3R,5R,6S)(3S,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-onewas obtained as the faster eluting isomer (less polar isomer) by silicagel chromatography.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.16-7.23 (2 H, m), 7.10-7.12 (1 H,m), 6.60 (1 H, d, J=4 Hz), 6.32 (1 H, d, J=4 Hz), 5.75-5.84 (1H, m),5.05-5.12 (2 H, m), 4.76 (1 h, d, J=8 Hz), 3.98-4.03 (1 H, m), 3.04-3.10(1 H, m), 2.75-2.81 (1 H, m), 2.51-2.63 (2H, m), 2.35-2.42 (1 H, m),2.05-2.11 (1 H, m), 1.89-1.99 (1 H, m), 0.88-0.98 (1 H, m), 0.49-0.56 (1H, m), 0.39-0.46 (1 H, m), 0.19-0.25 (1 H, m), 0.07-0.13 (1 H, m). MassSpectrum (ESI) m/z=420 (M+1).

The title compound (3S,5R,6S)(3R,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-onewas obtained as the slower eluting isomer on silica gel chromatography.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.42 (1 H, br s) 726-7.31 (1 H, m),7.19-7.23 (1 H, m),6.79 (1 H, d, J=4 Hz), 6.60 (1 H, d, J=4 Hz),5.70-5.80 (1H, m), 5.06-5.15 (3 H, m), 4.18-4.23 (1 H, m), 3.26-3.29 (1H, m), 2.62-2.68 (1 H, m), 2.41-2.51 (2H, m), 2.31-2.38 (1 H, m),2.15-2.22 (1 H, m), 1.92-1.98 (1 H, m), 1.11-1.21 (1 H, m), 0.63-0.69 (1H, m), 0.54-0.60 (1 H, m), 0.24-0.34 (2 H, m). Mass Spectrum (ESI)m/z=420 (M+1).

Step H.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from racemic(3R,5R,6S)(3S,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one(Example 63, Step G) as described in Example 1, Step H and resolved bychiral SFC on a CHRALCEL® OJ column (Daicel, Fort Lee, N.J.). It wasobtained as the slower eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.45 (1 H, br s) 7.31-7.34 (2 H,m), 7.23-7.35 (1 H, m),6.84 (1 H, d, J=4 Hz), 6.74 (1 H, d, J=4 Hz),5.27 (1 H, br s), 4.22-4.27 (1 H, m), 3.33 (1 H, br s), 2.76-2.84 (1 H,m), 2.52-2.63 (3H, m), 2.31-2.36 (1 H, m), 1.96-2.02 (1 H, m), 1.15-1.24(1 H, m), 0.71-0.77 (1 H, m), 0.60-0.67 (1 H, m), 0.34-0.40 (1 H, m),0.27-0.33 (1 H, m). Mass Spectrum (ESI) m/z=438 (M+1).

Example 642-((3S,5R,6S)-5-(3-chlorophenyl)-6-(5-chlorothiophen-2-yl)-1-(cyclopropylmethyl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from racemic(3R,5R,6S)(3S,5S,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-one(Example 63, Step G) as described in Example 1, Step H and resolved bychiral SFC on an AD column. It was obtained as the slower eluting isomeron a CHIRALCEL® (Daicel, Fort Lee, N.J.) AD column.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.17-7.24 (2 H, m), 7.09-7.10 (1 H,m), 6.90-6.92 (1H, m), 6.62 (1 H, d, J=4 Hz), 6.35 (1 H, d, J=4Hz), 4.80(1 H, d, J=12 Hz), 3.94-3.99 (1 H, m), 3.11-3.18 (1 H, m), 2.99-3.16 (1H, m), 2.54-2.66 (2H, m), 2.09-2.22 (2 H, m), 0.87-0.98 (1 H, m),0.50-0.57 (1 H, m), 0.40-0.47 (1 H, m), 0.18-0.24 (1 H, m), 0.07-0.13 (1H, m). Mass Spectrum (ESI) m/z=438 (M+1).

Example 65

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid Step A. (S)-Ethyl2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoateand (S)-Ethyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate

To a solution of 362 mg (833 μmol) of (S)-Ethyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate(Example 9, Step A) and allyl bromide (87 μl, 1000 μmol) in THF (3.30mL, 0.25 M) was added dropwise lithium bis(trimethylsilyl)amide (1Msolution in THF; 875 μl, 875 μmol) at −78° C. After being stirred at−78° C. for 3 h, the reaction was quenched (sat. aqueous NH₄Cl),extracted (2×EtOAc). The combined organic layers were washed with waterand sat. aq. NaCl solution, dried over Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure. Purification of the residue bychromatography (12 g SiO₂, 15 to 20% EtOAc/Hex, a gradient elution)provided the title compounds as a mixture of stereoisomers.

Step B. (2S)-Ethyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoateand (2S)-Ethyl2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

To a solution of 0.66 g (1.39 mmol) of (S)-ethyl2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate(Example 65, Step A; mixture of diastereomers) and iodomethane (0.592 g,4.17 mmol) in 15 mL of THF was added LHMDS (1.0M solution in THF; 4.17mL, 4.17 mmol) at RT. After being stirred for 12 h, the reaction wasquenched (sat. aqueous NH₄Cl), extracted (2×EtOAc). The combined organiclayers were washed with water and sat. aq. NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. Purification of the residue by reversed phase preparatory HPLC(Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 10to 90% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) gavethe title compound as a mixture of stereoisomers.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a rapidly stirring solution of 0.28 g (0.573 mmol) of (2S)-ethyl2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(Example 65, Step B; mixt. of diastereomers) in H₂O/CCl₄/MeCN(4.0/2.0/2.0, 8.0 mL) was added sodium periodate (0.490 g, 2.29 mmol),followed by ruthenium(III) chloride hydrate (0.013 g, 0.057 mmol). Afterbeing stirred vigorously for 12 h, the reaction was acidified (10%citric acid) and diluted with EtOAc. The insoluble material was removedby filtration through a pad of Celite® (J.T. Baker, Phillipsberg, N.J.,diatomaceous earth). The filtrate was extracted (2×EtOAc). The combinedorganic layers were washed with water and sat. aq. NaCl solution, driedover Na₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by reversed phase preparatory HPLC(Gemini™ Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 10to 90% acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) togive the title compound as the first eluting isomer as a white powder.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.59 (t, J=7.6 Hz, 3 H), 1.28 (t,J=7.2 Hz, 3 H), 1.44 (s, 3 H), 1.50-1.64 (m, 1 H), 2.10-2.19 (m, 1 H),2.19-2.37 (m, 2 H), 2.86 (q, J=14.5 Hz, 2 H), 3.19-3.35 (m, 2 H),4.11-4.27 (m, 2 H), 4.58 (d, J=10.5 Hz, 1 H), 6.77 (m, 1 H) 6.93-7.05(m, 3 H) 7.05-7.17 (m, 2 H) 7.20-7.33 (m, 2 H); MS (ESI) 506.2 [M+H]⁺.504.1 [M−H]⁻.

Example 66

2-((3S,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid Step A. (S)-tert-butyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate

The title compound was synthesized as described in Example 9, Step A,substituting ethyl 2-bromobutanoate for t-butyl 2-bromobutanoate.Purification by flash chromatography on silica gel (30% EtOAc/Hexanes)provided the title compound as the faster eluting component as a whitefoam.

Step B. (2S)-tert-butyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin-1-yl)butanoate

To a solution of 11.2 g (24.2 mmol) of (S)-tert-butyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate(Example 66, Step A) and iodomethane (1.813 mL, 29.1 mmol) in THF (120.0mL) was added a lithium bis(trimethylsilyl)amide, (1M solution in THF;26.6 mL, 26.6 mmol) at −78° C. The reaction was allowed to warm to R.T.,then was quenched (sat. aqueous NH₄Cl) and extracted (2×EtOAc). Thecombined organic layers were washed with water and sat. aq. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. The residue was absorbed onto a plug of silicagel and purified by chromatography on silica gel, eluting with agradient of 10% to 30% EtOAc in hexane, to provide the title compound asa mixture of stereoisomers.

Step C. (2S)-tert-butyl2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

To a solution of 10.2 g (21.4 mmol) of (2S)-tert-butyl2-(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin-1-yl)butanoate(Example 66, Step B, mixture of diastereomers) and allyl bromide (7.24mL, 86 mmol) in THF (210 mL) was added LHMDS, (1.0M solution in THF;64.2 mL, 64.2 mmol) at R.T. Let it stir at R.T. for 5 min. Then thereaction mixture was heated at 50° C. for 3 h. Sat. aq. NH₄Cl solutionwas added and the mixture was extracted with CH₂Cl₂. The combinedorganic layers were washed with water and sat. aq. NaCl solution, driedover MgSO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by chromatography, eluting with agradient of 0% to 20% EtOAc in hexane, to provide the title compound asa mixture of stereoisomers at C-3.

Step D.2-((3S,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

(2S)-tert-butyl2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(Example 66, Step C, mixture of diastereomers) was converted to the acidby a procedure similar to the one described in Example 65, Step D. Thecrude product was purified by reversed phase preparatory HPLC (Gemini™Prep C18 5 μm column, Phenomenex, Torrance, Calif.; eluent: 10 to 90%acetonitrile+0.1% TFA in water+0.1% TFA, gradient elution) to give, thetitle compound as the first eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.54 (t, J=7.5 Hz, 3 H), 1.41-1.55(m, 14 H), 2.07-2.17 (m, 1 H), 2.25 (d, J=13.5 Hz, 1 H), 2.28-2.42 (m, 1H), 2.81 (d, J=15.4 Hz, 1 H), 2.93-3.03 (m, 2 H), 3.24 (ddd, J=13.3,10.5, 3.1 Hz, 1 H), 4.58 (d, J=10.5 Hz, 1 H), 6.76 (m, 1 H) 6.97-7.06(m, 3 H) 7.08-7.20 (m, 2 H) 7.25 (s, 2 H); MS (ESI) 534.1 [M+H]⁺. 532.0[M−H]⁻.

Further elution provided Example 67.

Example 67

2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (t, J=7.5 Hz, 3 H), 1.43 (s, 9H), 1.50 (s, 3 H), 1.93-2.27 (m, 4 H), 2.79 (d, J=15.3 Hz, 1 H), 3.04(d, J=15.5 Hz, 1 H), 3.15-3.29 (m, 2 H), 4.52 (d, J=10.4 Hz, 1 H),6.68-6.78 (m, 1 H), 6.90-6.98 (m, 1 H), 7.05-7.29 (m, 6 H); MS (ESI)534.1 [M+H]⁺. 532.0 [M−H]⁻.

Example 68

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid Step A.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

To a solution of 3 g (6.9 mmol) of (S)-ethyl242S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate(Example 9, Step A) in 45 mL of Et₂O was added lithium tetrahydroborate(0.334 g, 13.81 mmol) at 0° C. After being stirred at 0° C. for 50 min,the reaction was quenched (ice cold 10% citric acid) and extracted(2×EtOAc). The combined organic layers were washed with water and sat.aq. NaCl solution, dried over MgSO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification by flashchromatography on silica gel (eluent: 30% to 60% EtOAc/Hexanes, gradientelution) provided the title compound.

Step B.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one

To a solution of 1.48 g (3.77 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-14S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 68, Step A) and bromomethylcyclopropane (0.828 mL, 7.54 mmol)in DMF (20 mL) was added sodium t-butoxide (0.544 g, 5.66 mmol) at 0° C.The mixture was stirred at 0° C. for 2 h and then warmed to rt. Then thereaction was stirred at rt for 14 h. The reaction was quenched with sat.aqueous NH₄Cl solution and extracted with EtOAc. The combined organiclayers were washed with water and sat. aq. NaCl solution, dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. Purification by flash chromatography on silica gel (eluent:20%-40% EtOAc/Hexanes, gradient elution) provided the title compound asa colorless oil.

Step C.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-3-methylpiperidin-2-one

To a solution of 0.325 g (0.73 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one(Example 68, Step B) and iodomethane (0.055 mL, 0.874 mmol) in THF (7.0mL) was added lithium bis(trimethylsilyl)amide (1M solution in THF, 0.8mL, 0.8 mmol) at −78° C. The reaction was allowed to warm to R.T., thenwas quenched with sat. aqueous NH₄Cl solution and extracted with EtOAc.The combined organic layers were washed with water and sat. aq. NaClsolution, dried over MgSO₄, filtered and the filtrate was concentratedunder reduced pressure.

The crude material was absorbed onto a plug of silica gel and purifiedby chromatography on silica gel, eluting with a gradient of 10% to 30%EtOAc in hexane, to provide the title compound as a mixture of C-3stereoisomers, as indicated by *.

Step D.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-3-methylpiperidin-2-one

To a solution of 0.2 g (0.434 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-3-methylpiperidin-2-one(Example 68, Step C, mixture of diastereomers) and allyl bromide (0.147mL, 1.737 mmol) in THF (5 mL) was added LHMDS, (1.0M solution in THF,1.3 mL, 1.3 mmol) at RT. Let it stir at RT for 5 min. Then the reactionmixture was heated at 50° C. for 3 h. The reaction mixture was dilutedwith satd. NH₄Cl. and extracted with CH₂Cl₂. The combined organic layerswere washed with water and sat. aq. NaCl solution, dried over MgSO₄,filtered and the filtrate was concentrated under reduced pressure. Thecrude material was purified by chromatography, eluting with a gradientof 0% to 20% EtOAc in hexane, to provide the title compound as acolorless oil.

Step E.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)-3-methylpiperidin-2-one(Example 68, Step E) was converted to the acid by a procedure similar tothe one described in Example 1, Step H, to provide the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.20-0.33 (m, 2 H), 0.51 (t, J=7.5Hz, 3 H), 0.57-0.70 (m, 2 H), 1.05-1.17 (m, 1 H), 1.44 (s, 3 H),1.48-1.62 (m, 1 H), 1.82-1.95 (m, 1 H), 2.01 (dd, J=13.9, 3.3 Hz, 1 H),2.20 (t, J=13.5 Hz, 1 H), 2.72 (d, J=15.1 Hz, 1 H), 2.95-3.12 (m, 3 H),3.24-3.40 (m, 3 H), 3.95 (t, J=9.8 Hz, 1 H), 4.69 (d, J=10.0 Hz, 1 H),6.72-6.80 (m, 1 H), 6.94-7.07 (m, 3 H), 7.07-7.21 (m, 2 H), 7.25 (d,J=8.61 Hz, 2 H);

Example 69

2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)aceticacid Step A.(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one

To a solution of 3.70 g (8.9 mmol) of a mixture of C-3 diastereomers of(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)piperidin-2-oneoxopentanoate(Example 35, Step B) and 20.7 g (63 mmol) of(2-iodoethoxy)triisopropylsilane in dry, degassed THF (60 mL) was added54.5 mL (54.5 mmol) of a 1 M solution of lithiumbis(trimethylsilyl)amide in THF slowly via syringe over 6 min. After 10min, the orange solution was warmed to 40° C. and stirred for anadditional 2.25 h. The reaction was cooled to room temperature, quenchedwith saturated aqueous ammonium chloride, and extracted with EtOAc (3×).The combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by flashchromatography on silica gel (2-25% EtOAc/hexanes, gradient elution)provided the title compound (mixture of C-3 epimers) as a light yellowoil.

Step B.2-((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde

To a solution of 1.28 g (2.08 mmol) of(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one(Example 69, Step A, mixture of diastereomers) in THF (50 mL) and water(17.5 mL) was added a catalytic amount of osmium tetroxide. After 25min, 1.34 g (6.25 mmol) of sodium periodate was added. The resultinglight brown slurry was stirred for 19 h and then was filtered through afitted funnel. The filtrate was partially concentrated under reducedpressure, then was diluted with water and extracted with ethyl acetate(2×). The combined organic layers were washed with saturated aqueoussodium thiosulfate and then saturated aqueous sodium chloride. Theorganic layer was dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The crude title compound (mixture of C-3 epimers) was useddirectly in the next step.

Step C. Synthesis of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-(pyrrolidin-1-yl)ethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one

A mixture of 1.02 g (1.66 mmol) of crude2-((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde(Example 69, Step B, mixture of diastereomers), 0.55 mL (6.6 mmol) ofpyrrolidine, 880 mg (4.15 mmol) of sodium triacetoxyborohydride and 285μL (4.98 mmol) of acetic acid was suspended in a mixture of1,2-dichloroethane (36 mL) and DMF (12 mL). After being stirred at roomtemperature for 20 h, the reaction mixture was quenched with saturatedaqueous sodium bicarbonate and extracted with DCM (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The crude title compound (mixture of C-3 epimers) was useddirectly in the next step.

Step D.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-hydroxyethyl)-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-2-one

To an ice-cooled solution of 1.12 g (1.66 mmol) of crude(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-(pyrrolidin-1-yl)ethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-2-one(Example 69, Step C, mixture of diastereomers) in THF (55 mL) added 8.3mL (8.3 mmol) of a 1M solution of TBAF in THF. After being stirred atroom temperature for 1.5 h, the reaction mixture was quenched with waterand extracted with EtOAc (3×). The combined organic layers were dried(Na₂SO₄), and concentrated under the reduced pressure. Purification ofthe residue by flash chromatography on silica gel (3-30% MeOH/DCM,gradient elution) provided the title compound (mixture of C-3 epimers)as a light yellow oil.

Step E.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)aceticacid

An ice-cooled solution of 2.05 g (20.5 mmol) of chromium(VI) oxide inwater (4 mL) was treated with 1.75 mL (32.7 mmol) of sulfuric acid viasyringe. The mixture was diluted with additional water (4 mL) and storedat 0° C. at prior to use. In a separate flask, 105 mg (0.21 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-hydroxyethyl)-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-2-one(Example 69, Step D, mixture of diastereomers) was dissolved in acetone(20 mL) and then treated with Jones reagent (see above) slowly viapipette at room temperature. After 30 min, the resulting dark redsolution was heated at 55° C. for an additional 17.5 h. The reaction wasconcentrated under reduced pressure, then was diluted with water andextracted with ethyl acetate (4×). The organic layers were over Na₂SO₄,filtered and the filtrate was concentrated. Purification of the residueby reversed phase prep. HPLC (Sunfire Prep C₁₈ OBD 10 μm column (Waters,Milford, Mass.), gradient elution of 40% MeCN in water to 55% MeCN inwater over a 35 min period, where both solvents contain 0.1% TFA)provided the title compound (single enantiomer) as a white solid. [Notethat the desired C-3 (3S) epimer is the less polar epimer and elutes offsecond].

¹H NMR (400 MHz, CDCl₃) δ ppm 11.11 (1 H, br s), 7.18-7.24 (2 H, m),7.08-7.18 (2 H, m), 6.99 (1 H, br s), 6.77-6.87 (3 H, m), 4.61 (1 H, dd,J=10.1 Hz, 4.7 Hz), 3.72-3.86 (3 H, m), 3.61 (1 H, br s), 3.36 (1 H, brs), 3.13 (1 H, br s), 2.75-2.97 (4 H, m), 2.20-2.35 (2 H, m), 1.99-2.22(7 H, m), 0.84 (1 H, br s), 0.36-0.54 (2 H, m), −0.05-0.13 (2 H, m).Mass Spectrum (ESI) m/z=529 (M+1).

Example 70

2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)aceticacid Step A.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-hydroxyethyl)-3-(2-morpholinoethyl)piperidin-2-one

A mixture of 94 mg (0.15 mmol) of crude245R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-3-yl)acetaldehyde(Example 69, Step B, mixture of diastereomers), 66 μL (0.76 mmol) ofmorpholine, 97 mg (0.46 mmol) of sodium triacetoxyborohydride and 30 μL(0.53 mmol) of acetic acid was suspended in a mixture of1,2-dichloroethane (6 mL) and DMF (2 mL). After being stirred at roomtemperature for 20 h, the reaction mixture was quenched with saturatedaqueous sodium bicarbonate and extracted with DCM (3×). The combinedorganic layers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated. Purification of the residue by reversed phase preparatoryHPLC (SunFire™ Prep C₁₈ OBD 10 μm column (Waters, Milford, Mass.),gradient elution of 50% MeCN in water to 90% MeCN in water over a 30 minperiod, where both solvents contain 0.1% TFA) provided the titlecompound (mixture of C-3 epimers) along with the corresponding TIPSether (mixture of C-3 epimers) and the corresponding trifluoroacetate(mixture of C-3 epimers) as a colorless oil.

This mixture was dissolved in THF (5 mL) and treated with 0.76 mL (0.76mmol) of a 1M solution of TBAF in THF. After being stirred at roomtemperature for 3.5 h, the reaction mixture was quenched with water andextracted with EtOAc (3×). The combined organic layers were dried(Na₂SO₄), and concentrated under the reduced pressure. Purification ofthe residue by flash chromatography on silica gel (8-35% MeOH/DCM,gradient elution) provided the title compound (mixture of C-3 epimers)as a white solid.

Step B.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)aceticacid

An ice-cooled solution of 403 mg (4.03 mmol) of chromium(VI) oxide inwater (1 mL) was treated with 343 μL (6.44 mmol) of sulfuric acid viasyringe. The solution was diluted with additional water (1 mL) andstored at 0° C. at prior to use. In a separate flask,(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-(2-hydroxyethyl)-3-(2-morpholinoethyl)piperidin-2-one(Example 70, Step A, mixture of diastereomers) was dissolved in acetone(5 mL) and then treated with Jones reagent (see above) slowly viapipette at room temperature. After 30 min, the resulting dark redsolution was heated at 55° C. for an additional 17 h. The reaction wasconcentrated under reduced pressure, then was diluted with water andextracted with ethyl acetate (3×). The organic layers were over Na₂SO₄,filtered and the filtrate was concentrated. Purification of the residueby reversed phase prep. HPLC (SunFire™ Prep C₁₈ OBD 10 μm column(Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 60%MeCN in water over a 35 min period, where both solvents contain 0.1%TFA) provided the title compound (single enantiomer) as a white solid.[Note that the desired (3S)C-3 epimer is the less polar epimer andelutes off second].

¹H NMR (400 MHz, CDCl₃) δ ppm 12.05 (1 H, br s), 6.95-7.26 (5 H, m),6.76-6.88 (3 H, m), 4.64 (1 H, d, J=10.0 Hz), 4.23 (1 H, br s),3.76-4.10 (5 H, m), 3.43-3.65 (2 H, m), 3.08-3.34 (2 H, m), 2.78-3.01 (3H, m), 2.41-2.76 (2 H, m), 2.26-2.39 (2 H, m), 2.08-2.24 (2 H, m), 0.85(1 H, br s), 0.33-0.55 (2 H, m), −0.10-0.15 (2 H, m). Mass Spectrum(ESI) m/z=545 (M+1).

Example 71

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid Step A.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one

Thionyl chloride (116 mL, 1586 mmol) was added dropwise over 1 hour to aturbid solution of (2,4-dimethoxyphenyl)methanol (97.00 g, 577 mmol) andpyridine (93 mL, 1153 mmol) in anhydrous Et₂O (1153 mL) at 0° C. undernitrogen with mechanical stirring. After 1 hour the reaction mixture waspoured into 2 L of ice water and the layers were separated. The aqueouslayer was extracted with Et₂O (2×1 L) and the organics were pooled,washed with ice water (1.2 L), cold 5:1 sat. aq. NaCl solution/sat. aq.NaHCO₃ (1.2 L), dried (MgSO₄), filtered and most of the ether wasremoved in vacuo at 12° C. Benzene (300 mL) was added and the mixturewas concentrated at 12° C. until 100 mL of benzene remained to provide asolution of 1-(chloromethyl)-2,4-dimethoxybenzene.

80 g (250 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1,Step E) was added in portions over 20 minutes to a mixture of NaH (19.98g, 500 mmol) in anhydrous DMF (400 mL) at 0° C. under nitrogen. Afterthe addition was complete the ice bath was removed and the mixture wasstirred at rt for 1 hour before cooling the solution to 0° C. To thecooled solution was added a solution of1-(chloromethyl)-2,4-dimethoxybenzene (107 g, 575 mmol) in benzene andthe reaction mixture was allowed to warm to rt. After 16 hours thereaction mixture was poured into ice water (2 L) and extracted withEtOAc (3×1 L). The organics were pooled, washed with water (3×1 L), sat.aq. NaCl solution (1 L), dried (MgSO₄), filtered and concentrated invacuo to provide a thick yellow oil. Purification on the Combiflash XL(flash column chromatography, Teledyne Isco, Lincoln, Nebr.) using fourstacked 330 g columns and one 1.5 kg column and eluting with35-40-45-50-55% EtOAc/hexanes provided a very pale yellow oil. This wasdissolved in benzene and the solvent removed in vacuo and dried undervacuum for 2 days to provide the title compound as a white foam (105.8g, 90%).

Step B.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one

A solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)piperidin-2-one(Example 71, Step A) (140.34 g, 298 mmol) in anhydrous THF (994 mL) wasdegassed by bubbling argon through the solution for 20 minutes while itcooled to −78° C. Iodomethane (23.32 mL, 373 mmol) was added followed bythe addition of LHMDS (328 mL, 328 mmol) over 15 minutes. The reactionmixture was stirred for 15 minutes at −78° C. and then the reaction wasremoved from the cold bath and stirred at rt for 12 hours. The reactionwas quenched by the addition of sat. aq. NH₄Cl and the layers wereseparated. The aqueous layer was extracted with EtOAc (2×500 mL) and theorganics were pooled, washed with sat. aq. NaCl solution, dried (MgSO₄),filtered and concentrated in vacuo to provide an orange oil.Purification (wet loaded with small amount of DCM) using the CombiflashCompanion XL (flash column chromatography, Teledyne Isco, Lincoln,Nebr.) with a 1.5 kg SiO₂ column and eluting with 4 L each of15-20-25-30-35% EtOAc/hexanes provided the title compound as a thickvery pale yellow oil and a 3.7:1 mixture of C-3 diastereomers.

Step C.(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one

A solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one(Example 71, Step B, mixture of C-3 diastereomers) (117.0 g, 242 mmol)in anhydrous THF (966 mL) was degassed by bubbling argon through thesolution for 20 minutes. Allyl bromide (105 mL, 1208 mmol) was addedfollowed by the addition of LHMDS (725 mL, 725 mmol) over 20 minutes.The reaction mixture was heated at 40° C. under argon for 5 hours. Thereaction mixture was cooled to rt. and the reaction was quenched by theaddition of sat. aqueous NH₄Cl (500 mL) and the layers were separated.The aqueous layer was extracted with EtOAc (2×1 L) and the organics werepooled, washed with sat. aq. NaCl solution (1 L), dried (MgSO₄),filtered and concentrated in vacuo to provide a red oil (180 g).Purification using the Biotage system (Charlotte, N.C.) with a 1.5 kgSiO₂ column and eluting with 10-30% EtOAc/hexanes provided the titlecompound as a very pale yellow oil as a 3.7:1 mixture of (3S):(3R)diastereomers.

Step D.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

A solution of(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one(Example 71, Step C, mixture of diastereomers) (105.87 g, 202 mmol) inTFA (778 mL, 1.01E+04 mmol) was heated at 50° C. for 2 hours beforeconcentrating the reaction mixture in vacuo. The residue was azeotropedwith hexanes to remove all of the TFA. The deep purple oil containingsome residue was taken up in a minimum amount of DCM, filtered andwashed liberally with DCM. The filtrate was concentrated in vacuo toprovide a dark purple oil. Purification (wet packed with a minimumamount of DCM) using the Biotage Isolera (Biotage, Charlotte, N.C.) witha 1.5 kg column and eluting with 25-40% EtOAc/hexanes provided the titlecompound as a white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 1.30 (s, 3H), 2.06 (m, 2H), 2.52 (dd,J=13.7 and 7.1 Hz, 1H), 2.60 (dd, J=13.7 and 7.8 Hz, 1H), 3.06 (m, 1H),4.50 (d, J=10.7 Hz, 1H), 5.17 (m, 2H), 5.81 (br s, 1H), 5.86 (m, 1H),6.77 (d, J=7.6 Hz, 1H), 6.96 (d, J=8.3 Hz, 2H), 7.00 (s, 1H), 7.12 (t,J=7.7 Hz, 1H), 7.17 (m, 1H), 7.20 (d, J=8.3 Hz, 2H). [ ]²² _(D)=+182.2°(c 1.55, CHCl₃).

Step E.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one

To a suspension of 1.81 g (4.8 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) in 3-bromopentane (17.6 mL) added 967 mg (60 wt. %in mineral oil, 24.2 mmol) of sodium hydride. The resulting milky whiteslurry was heated at 120° C. for 20 h, and then more 3-bromopentane (5.1mL) was added. After an additional 24 h at 120° C., the reaction wascooled to room temperature and quenched with saturated aqueous ammoniumchloride. The mixture was extracted with ethyl acetate (3×) and thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by flashchromatography on silica gel (2 to 26% EtOAc/hexanes, gradient elution)provided the title compound as a white solid.

Step F. Synthesis of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid

To a solution of 725 mg (1.63 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one(Example 3, Step A) in a mixture of acetonitrile (4 mL), carbontetrachloride (4 mL) and water (5.9 mL) added 1.40 g (6.53 mmol) ofsodium periodate followed by 44 mg (0.20 mmol) of ruthenium(III)chloride hydrate. The dark brown biphasic mixture was stirred vigorouslyat room temperature for 21 h, and then was acidified with 1 N HCl. Themixture was diluted with EtOAc and filtered through a pad of Celite®(J.T. Baker, Phillipsberg, N.J., diatomaceous earth). After filtration,the layers were separated and the aqueous layer was extracted with EtOAc(1×). The combined organic layers were washed with saturated aqueoussodium chloride (1×), then were dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by flashchromatography on silica gel (0 to 25% MeOH/DCM, gradient elution)provided the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.06-7.27 (5 H, m), 6.90-7.01 (2 H, m),6.68 (d, 1 H, J=7.8 Hz), 4.34 (1 H, d, J=10.4 Hz), 3.00-3.15 (2 H, m),2.63-2.79 (2 H, m), 2.15-2.27 (1 H, m), 1.85-2.03 (3 H, m), 1.51 (s, 3H), 1.38-1.51 (2 H, m), 0.95 (3 H, t, J=7.4 Hz), 0.50 (3 H, t, J=7.4Hz). Mass Spectrum (ESI) m/z=462 (M+1).

Examples 72-75 were prepared in a process similar to that described forExample 71, substituting 3-bromopentane in Step E for the appropriateamount of alkylhalide.

Example R¹ 72

73

74

75

Example 722-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29 (2 H, d, J=8.6 Hz), 7.12-7.24(3 H, m), 6.90 (2 H, d, J=8.6 Hz), 6.88-6.82 (1 H, m), 4.80 (1 H, d,J=8.4 Hz), 4.02 (1 H, dd, J=14.1, 6.8 Hz), 3.11-3.03 (1 H, m), 2.98 (1H, d, J=15.5 Hz), 2.68 (1 H, d, J=15.5 Hz), 2.37 (1 H, dd, J=14.1, 7.4Hz), 2.23-2.14 (1 H, m), 2.13-2.05 (1 H, m), 1.39 (3 H, s), 1.03-0.94 (1H, m), 0.62-0.46 (2 H, m), 0.23-0.08 (1 H, m); MS (ESI) 446.0 [M+H]⁺,444.1 [M−H]⁻.

Example 732-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27 (2 H, d, J=7.8 Hz), 7.14-7.20(2 H, m), 7.02 (1 H, s), 6.97 (2 H, d, J=7.8 Hz), 6.75 (1 H, d, J=7.6Hz), 4.49 (1 H, d, J=9.0 Hz), 3.45 (1 H, m), 3.08 (1 H, m), 2.98 (1 H,d, J=15.2 Hz), 2.77 (1 H, d, J=15.2 Hz), 2.08 (2 H, m), 1.38 (3 H, s),1.24 (6 H, t, J=6.7 Hz); MS (ESI) 434.0 [M+H]⁺.

Example 742-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclobutyl-3-methyl-2-oxopiperidin-3-yl)aceticacid

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15-7.26 (3 H, m), 7.17 (1 H, m),7.04 (1 H, s), 6.65-6.79 (3 H, m), 4.65 (1 H, d, J=8.8 Hz), 3.85 (1 H,m), 3.05 (1 H, d, J=15.8 Hz), 2.85 (1 H, m), 2.60 (1 H, d, J=15.8 Hz),2.45 (1 H, m), 2.20 (1 H, m), 1.90-2.2.20 (2 H, m), 1.65 (1 H, m),1.42-1.55 (3 H, m), 1.42 (3 H, s); MS (ESI) 446.0 [M+H]⁺.

Example 752-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-cyclopentyl-3-methyl-2-oxopiperidin-3-yl)aceticacid

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.28 (2 H, d, J=8.3 Hz), 7.14-7.25(2 H, m), 7.06 (1 H, s), 6.93 (2 H, d, J=8.3 Hz), 6.80 (1 H, d, J=7.6Hz), 4.63 (1 H, d, J=8.1 Hz), 3.40 (1 H, m), 3.03 (1 H, d, J=15.7 Hz),3.02 (1 H, m), 2.62 (1 H, d, J=15.7 Hz), 1.75-2.13 (7 H, m), 1.26-1.45(3 H, m), 1.33 (3 H, s); MS (ESI) 460.1 [M+H]⁺.

Example 76

(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-oneStep A.2-(2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetyl)hydrazinecarboxamide

To a solution of 320 mg (0.69 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid (Example 71, Step F) and 921 mg (2.42 mmol) of HOBt in DMF (13 mL)was added 0.58 mL (4.15 mmol) of triethylamine. After stirring at roomtemperature for 40 min, added 270 mg (2.42 mmol) of semicarbazidehydrochloride. The resulting dark red solution was stirred at roomtemperature for 2.5 h, and then was concentrated under reduced pressure.Purification of the residue by reversed phase prep. HPLC (Sunfire™ PrepC₁₈ OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40%MeCN in water to 90% MeCN in water over a 30 min period, where bothsolvents contain 0.1% TFA) provided the title compound as a light yellowsolid.

Step B.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-((5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl)-1-(pentan-3-yl)piperidin-2-one

259 mg (0.50 mmol) of2-(2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetyl)hydrazinecarboxamide(Example 76, Step A) was suspended in 2 N aqueous sodium hydroxide (16mL) and heated at reflux for 3.25 h. Upon cooling to room temperature,the mixture was acidified with conc. HCl until strongly acidic and thenextracted with EtOAc (3×). The combined organic layers were dried over

Na₂SO₄, filtered and the filtrate was concentrated. Purification of theresidue by reversed phase prep. HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column(Waters, Milford, Mass.), gradient elution of 40% MeCN in water to 75%MeCN in water over a 30 min period, where both solvents contain 0.1%TFA) provided the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 10.36 (1 H, br s), 9.35 (1 H, br s),7.20-7.27 (3 H, m), 7.05-7.17 (2 H, m), 6.86-6.95 (2 H, m), 6.68 (1 H,d, J=7.8 Hz), 4.34 (1 H, d, J=10.5 Hz), 2.90-3.09 (3 H, m), 2.68-2.76 (1H, m), 2.21 (1 H, t, J=13.8 Hz), 2.05 (1 H, dd, J=13.9 Hz, 2.9 Hz)1.85-1.99 (2 H, m), 1.37-1.52 (2 H, m), 1.36 (3 H, s), 0.94 (3 H, t,J=7.4 Hz), 0.50 (3 H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=501 (M+1),523 (M+23).

Example 77

5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,3,4-oxadiazol-2(3H)-one

A solution of 56 mg (0.19 mmol) of triphosgene in DCM (1 mL) was addeddropwise to a solution of 62 mg (0.13 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetohydrazide(obtained as a byproduct in Example 76, Step B) and 170 μL (0.98 mmol)of diisopropylethylamine in DCM (4 mL). The resulting light yellowsolution was stirred at room temperature for 18 h, then was quenchedwith saturated aqueous sodium bicarbonate and extracted with EtOAc (3×).The combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by reversed phasepreparative HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column, (Waters, Milford,Mass.) gradient elution of 40% MeCN in water to 75% MeCN in water over a30 min period, where both solvents contain 0.1% TFA) provided the titlecompound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 9.68 (1 H, br s), 7.08-7.27 (4 H, m),6.90-7.01 (3 H, m), 6.70 (1 H, d, J=7.4 Hz), 4.35 (1 H, d, J=10.4 Hz),3.01-3.15 (3 H, m), 2.70-2.79 (1 H, m), 2.15 (1 H, t, J=13.8 Hz), 2.01(1 H, dd, J=13.8 Hz, 3.1 Hz) 1.82-1.95 (2 H, m), 1.35-1.57 (2 H, m),1.43 (3 H, s), 0.93 (3 H, t, J=7.4 Hz), 0.51 (3 H, t, J=7.4 Hz). MassSpectrum (ESI) m/z=502 (M+1).

Example 78

2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N-(trifluoromethylsulfonyl)acetamide

To a solution of 47 mg (0.10 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid (Example 71, Step F) in DMF (4 mL) was added 64 mg (0.34 mmol) ofEDC, 48 mg (0.36 mmol) of HOBt, and a catalytic amount of DMAP. After 30min, 45.5 mg (0.30 mmol) of trifluoromethanesulfonamide was added. Theresulting light yellow solution was stirred at room temperature for 3 h,and then was concentrated under reduced pressure. Purification of theresidue by reversed phase prep. HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column(Waters, Milford, Mass.), gradient elution of 50% MeCN in water to 90%MeCN in water over a 30 min period, where both solvents contain 0.1%TFA) provided the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.25-7.32 (3 H, m), 7.16-7.20 (1 H, m),7.11 (t, 1 H, J=7.8 Hz), 6.92-7.00 (2 H, m), 6.67 (d, 1 H, J=7.6 Hz),4.35 (1 H, d, J=10.4 Hz), 3.19 (d, 1 H, J=15.7 Hz), 2.97-3.06 (1 H, m),2.73-2.83 (1 H, m), 2.68 (1 H, d, J=15.7 Hz), 2.26 (1 H, t, J=13.8 Hz),1.86-2.08 (3 H, m), 1.52 (3 H, s), 1.39-1.52 (2 H, m), 0.95 (3 H, t,J=7.4 Hz), 0.50 (3 H, t, J=7.4 Hz). Mass Spectrum (ESI) m/z=593 (M+1),615 (M+23).

Example 79

(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-pyrazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-oneStep A.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetaldehyde

To a solution of 240 mg (0.54 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one(Example 71, Step E) in THF (8 mL) and water (2.8 mL) added a catalyticamount of osmium tetroxide. After 1.25 h, 323 mg (1.51 mmol) of sodiumperiodate were added. The resulting light brown slurry was stirred atroom temperature for 18.5 h, and then filtered through a fritted funnel.The filtrate was partially concentrated under reduced pressure, then wasdiluted with water and extracted with ethyl acetate (2×). The combinedorganic layers were washed with saturated aqueous sodium thiosulfate andthen saturated aqueous sodium chloride. The organic layer was dried overNa₂SO₄, filtered and the filtrate was concentrated. The crude titlecompound was used directly in the next step.

Step B. Ethyl4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-3-oxobutanoate

To a suspension of 160 mg (0.36 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetaldehyde(Example 79, Step A) and 20.4 mg (0.11 mmol) of tin(II) chloride in DCM(6 mL) was added 104 μL (1.00 mmol) of ethyl diazoacetate via syringeover 3 min. The resulting yellow slurry was stirred at room temperaturefor 14.25 h, then was quenched with 1 N HCl and extracted with EtOAc(2×). The combined organic layers were washed with 1 N HCl (1×), thenwere dried over Na₂SO₄, filtered and the filtrate was concentrated.Purification of the residue by reversed phase prep. HPLC (Sunfire™ PrepC₁₈ OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 55%MeCN in water to 85% MeCN in water over a 30 min period, where bothsolvents contain 0.1% TFA) provided the title compound as a light yellowoil.

Step C.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxy-1H-pyrazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one

To a solution of 42 mg (0.08 mmol) of ethyl4-43R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-3-oxobutanoate(Example 79, Step B) in ethanol (4 mL) was added 36 μL (0.48 mmol)hydrazine monohydrate (64-65% weight percent hydrazine). The resultingcolorless solution was heated at 65° C. for 3.5 h, and then wasconcentrated under reduced pressure. Purification of the residue byreversed phase prep. HPLC (Sunfire Prep C₁₈ OBD 10 μm column, gradientelution of 45% MeCN in water to 80% MeCN in water over a 30 min period,where both solvents contain 0.1% TFA) provided the title compound as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.23-7.30 (3 H, m), 7.18-7.22 (1 H, m),7.12 (1 H, t, J=7.7 Hz), 6.90-6.96 (2 H, m), 6.67 (1 H, d, J=7.8 Hz),5.66 (1 H, s), 4.34 (1 H, d, J=10.6 Hz), 3.42 (1 H, d, J=15.9 Hz),3.02-3.11 (1 H, m), 2.82 (1 H, d, J=15.9 Hz), 2.68-2.77 (1 H, m), 2.36(1 H, t, J=13.9 Hz), 1.87-2.03 (3 H, m), 1.40-1.51 (2 H, m), 1.36 (3 H,s), 0.96 (3 H, t, J=7.4 Hz), 0.50 (3 H, t, J=7.5 Hz). Mass Spectrum(ESI) m/z=500 (M+1), 522 (M+23).

Example 80

(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((3-hydroxyisoxazol-5-yl)methyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one

To an ice-cooled slurry of 65 mg (0.12 mmol) of ethyl4-43R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-3-oxobutanoate(Example 79, Step B) in water (2 mL) was added 53.5 mg (0.77 mmol) ofhydroxylamine hydrochloride and 62 mg (1.55 mmol) of sodium hydroxide.After 5 min, THF (1 mL) and MeOH (1 mL) were added. The resulting cloudylight yellow solution was stirred at 0° C. for 20 min, then was warmedto room temperature and stirred for an additional 6 h. The reaction wasacidified by dropwise addition of conc. HCl until strongly acidic, thenwas diluted with water and extracted with EtOAc (4×). The combinedorganic layers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated. Purification of the residue by reversed phase prep. HPLC(Sunfire™ Prep C₁₈ OBD 10 μm column (Waters, Milford, Mass.), gradientelution of 55% MeCN in water to 85% MeCN in water over a 30 min period,where both solvents contain 0.1% TFA) provided the title compound as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.20-7.27 (3 H, m), 7.14-7.20 (1 H, m),7.11 (1 H, dt, J=7.8 Hz, 3.8 Hz), 6.89-7.01 (3 H, m), 6.70 (1 H, d,J=7.4 Hz), 4.33 (1 H, dd, J=10.5 Hz, 3.4 Hz), 3.59-3.78 (2 H, m),3.13-3.23 (1 H, m), 3.07 (1 H, dd, J=14.1 Hz, 3.1 Hz), 2.66-2.77 (2 H,m), 2.15-2.26 (1 H, m), 1.96-2.04 (1 H, m), 1.78-1.94 (2 H, m),1.40-1.51 (1 H, m), 1.41 (3 H, s), 0.93 (3 H, dt, J=7.4 Hz, 3.5 Hz),0.51 (3 H, dt, J=7.5 Hz, 3.6 Hz). Mass Spectrum (ESI) m/z=501 (M+1).

Example 81

5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)oxazolidine-2,4-dioneStep A.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one

To a solution of 298 mg (0.67 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one(Example 71, Step E) in a mixture of acetone (11.5 mL) and water (4 mL)added a catalytic amount of osmium tetroxide. After 4 min, 275 mg (2.35mmol) of N-methylmorpholine-N-oxide was added. The resulting brownsolution was stirred at room temperature for 3.5 h, and then waspartitioned between water and DCM (3×). The combined organic layers weredried over Na₂SO₄, filtered and the filtrate was concentrated.Purification of the residue by flash chromatography on silica gel (1 to20% MeOH/DCM, gradient elution) provided the title compound (mixture ofalcohol epimers) as a yellow oil.

Step B.3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanoicacid

A mixture of 142 mg (0.30 mmol) of(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one(Example 81, Step A) and 28 mg (0.18 mmol) of TEMPO in a mixture ofacetonitrile (6 mL) and sodium phosphate-sodium hydroxide buffer (pH6.7, 4.5 mL) at 35° C. was treated simultaneously with a solution of 105mg (1.16 mmol) of sodium chlorite in water (1.2 mL) and a solution of106 lat (0.07 mmol) of bleach solution (ca. 0.7 N) in water (0.6 mL)over 10 min. The resulting dark orange solution was stirred at 35° C.for 1.75 h, and then was partitioned between 1 N HCl and EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by reversed phaseprep. HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column (Waters, Milford, Mass.),gradient elution of 60% MeCN in water to 80% MeCN in water over a 30 minperiod, where both solvents contain 0.1% TFA) provided the titlecompound (mixture of alcohol epimers) as a white solid.

Step C.3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N-(2,4-dimethoxybenzyl)-2-hydroxypropanamide

To a solution of 43 mg (0.09 mmol) of3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanoicacid (Example 81, Step B) in DMF (5 mL) was added 67 mg (0.18 mmol) ofHATU, 58.5 mg (0.35 mmol) of 2,4-dimethoxybenzylamine and 36 μL (0.26mmol) of triethylamine. The resulting yellow solution was stirred atroom temperature for 1.1 h, and then was partitioned between saturatedaqueous sodium bicarbonate and EtOAc (2×). The combined organic layerswere dried over Na₂SO₄, filtered and the filtrate was concentrated. Thecrude title compound (mixture of alcohol epimers) was used directly inthe next step.

Step D.(S)-3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanamideand(R)-3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanamide

A solution of 56 mg (0.09 mmol) of3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N-(2,4-dimethoxybenzyl)-2-hydroxypropanamide(Example 81, Step C) in trifluoroacetic acid (2.3 mL) was heated at 50°C. for 2.5 h, and then was concentrated under reduced pressure.Purification of the residue by reversed phase prep. HPLC (Sunfire™ PrepC₁₈ OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 50%MeCN in water to 75% MeCN in water over a 30 min period, where bothsolvents contain 0.1% TFA) provided the two title compounds (in eachcase the stereochemistry at alcohol stereocenter is arbitrarilyassigned) each as a light green solid.

Step E.5-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)oxazolidine-2,4-dione

To a solution of 10.3 mg (0.02 mmol) of(S)-3-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-2-hydroxypropanamide(Example 81, Step D) in MeOH (2.5 mL) was added 0.50 mL (1.22 mmol) ofsodium ethoxide (21 wt. % solution in ethanol) and 1.20 mL (9.90 mmol)of diethyl carbonate. The resulting mixture was heated at reflux for 15min, and then was concentrated under reduced pressure. The residue waspartitioned between 0.5 M HCl and EtOAc (3×). The combined organiclayers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated. Purification of the residue by reversed phase prep. HPLC(Sunfire™ Prep C₁₈ OBD 10 μm column (Waters, Milford, Mass.), gradientelution of 60 MeCN in water to 80 MeCN in water over a 30 min period,where both solvents contain 0.1% TFA) provided the title compound(mixture of ether epimers) as a white solid.

¹H NMR (400 MHz, CDCl₃, mixture of epimers) δ ppm 8.90 (1 H, br s, majorepimer), 8.83 (1 H, br s, minor epimer), 7.20-7.27 (3 H, m), 7.15-7.20(1 H, m), 7.11 (1 H, dt, J=7.7 Hz, 1.9 Hz), 6.94-7.02 (2 H, m), 6.71 (1H, d, J=7.6 Hz), 5.37 (1 H, t, J=10.0 Hz), 4.33 (1 H, d, J=10.4 Hz),2.67-2.79 (1 H, m), 2.67-2.79 (1 H, m, major epimer) 2.41 (1 H, dd,J=15.2 Hz, 8.6 Hz, minor epimer), 1.82-2.31 (6 H, m), 1.48-1.61 (1 H,m), 1.35-1.45 (1 H, m), 1.45 (3 H, s, minor epimer), 1.44 (s, 3 H, majorepimer), 0.94 (3 H, t, J=7.4 Hz), 0.52 (3 H, t, J=7.5 Hz). Mass Spectrum(ESI) m/z=517 (M+1), 539 (M+23).

Example 823-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one

Step A.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3yl)piperidin-3-yl)acetamide

To an ice-cooled solution of 1.15 g (2.49 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid (Example 71, Step F) in THF (12.5 mL) was added 383 μL (3.48 mmol)of N-methylmorpholine and 392 μL (2.98 mmol) of isobutyl chloroformate.The resulting off-white slurry was stirred at 0° C. for 2 h, and then336 μL (28% ammonia in water, 4.97 mmol) of ammonium hydroxide wasadded. After an additional 3 h at 0° C., the reaction was quenched withsaturated aqueous ammonium chloride and extracted with EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. The crude title compound was used directly inthe next step.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetonitrile

To an ice-cooled solution of 1.15 g (2.49 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetamide(Example 82, Step A) in THF (21 mL) was added 1.73 mL (12.4 mmol) oftriethylamine and 865 μL (6.22 mmol) of TFA. The resulting tan solutionwas stirred at 0° C. for 2.75 h, then was warmed to room temperature andstirred for an additional 2 h. The reaction was recooled to 0° C.,quenched with 1 N citric acid, and then extracted with EtOAc (3×). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. The combined organic layers were washed withsaturated aqueous sodium chloride (1×), then were dried over Na₂SO₄,filtered and the filtrate was concentrated. Purification of the residueby flash chromatography on silica gel (5 to 35% EtOAc/hexanes, gradientelution) provided the title compound as a white solid.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N′-hydroxyacetimidamide

To a suspension of 1.49 g (20.6 mmol) of hydroxylamine hydrochloride inDMSO (10 mL) was added 2.88 mL (20.6 mmol) of triethylamine. The slurrywas stirred for 5 min and then filtered twice through cotton, rinsingwith THF, to remove the solids. The filtrate was partially concentratedunder reduced pressure to remove THF, and then was added to a flaskcontaining 915 mg (2.06 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)acetonitrile(Example 82, Step B). The resulting yellow solution was heated at 75° C.for 22 h, and then was partitioned between water and EtOAc. The organiclayer was dried over Na₂SO₄, filtered and the filtrate was concentrated.Purification of the residue by flash chromatography on silica gel (1 to7% MeOH/DCM, gradient elution) provided the title compound as a whitesolid.

Step D.3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one

To a solution of 385 mg (0.81 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N′-hydroxyacetimidamide(Example 82, Step C) in dioxane (12.5 mL) was added 211 μL (1.41 mmol)of DBU and 262 mg (1.62 mmol) of 1,1′-carbonyldiimidazole. The resultingcolorless solution was heated at 100° C. for 25 min, and then wasquenched with water and extracted with EtOAc. The organic layer waswashed with saturated aqueous sodium chloride, and then was dried overNa₂SO₄, filtered and the filtrate was concentrated. Purification of theresidue by reversed phase prep. HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column(Waters, Mlford, Mass.), gradient elution of 55% MeCN in water to 80%MeCN in water over a 35 min period, where both solvents contain 0.1%TFA) provided the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 10.39 (1 H, br s), 7.22-7.27 (3 H, m),7.18 (1 H, d, J=8.1 Hz), 7.12 (1 H, t, J=7.8 Hz), 6.87-6.98 (2 H, m),6.68 (1 H, d, J=7.6 Hz), 4.35 (1 H, d, J=10.3 Hz), 3.19 (1 H, d, J=15.4Hz), 3.05 (1 H, ddd, J=13.3 Hz, 10.5 Hz, 2.6 Hz), 2.82 (1 H, d, J=15.4Hz), 2.69-2.78 (1 H, m), 2.31 (1 H, t, J=13.8 Hz), 2.06 (1 H, dd, J=13.9Hz, 2.7 Hz), 1.84-2.00 (2 H, m), 1.39-1.51 (2 H, m), 1.38 (3 H, s), 0.95(3 H, t, J=7.5 Hz), 0.50 (3 H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=502(M+1), 524 (M+23).

Example 833-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared by methods similar to those described inExample 82. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.38 (1 H, br s), 7.24-7.32(2 H, m), 7.18-7.23 (m, 1 H), 7.15 (1 H, dt, J=7.8 Hz, 3.6 Hz), 7.04 (1H, br s), 6.90 (2 H, d, J=5.4 Hz), 6.76 (1 H, d, J=7.1 Hz), 4.52 (1 H,dd, J=8.6 Hz, 3.2 Hz), 3.40-3.50 (1 H, m), 3.09 (1 H, dd, J=15.3 Hz, 2.8Hz), 2.99-3.06 (1 H, m), 2.78 (1 H, dd, J=15.3 Hz, 3.1 Hz), 2.18 (1 H,dt, J=11.9 Hz, 3.2 Hz), 2.05-2.13 (1 H, m), 1.22-1.27 (m, 9 H). MassSpectrum (ESI) m/z=474 (M+1).

Example 84

3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one

To a solution of 83 mg (0.17 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)-N′-hydroxyacetimidamide(Example 82, Step C) in THF (4 mL) was added 50 mg (0.28 mmol) of1,1′-thiocarbonyldiimidazole. The resulting yellow solution was stirredat room temperature for 1 h, and then was quenched with water andextracted with EtOAc. The organic layer was dried over Na₂SO₄, filteredand the filtrate was concentrated. The residue was dissolved in THF (4.5mL), and 69 μL (0.56 mmol) of boron trifluoride etherate was added viasyringe. The resulting light yellow solution was stirred at roomtemperature for 2.5 h, and then was quenched with water and extractedwith EtOAc. The organic layer was dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by reversed phaseprep. HPLC (Sunfire Prep C₁₈ OBD 10 μm column, gradient elution of 55%MeCN in water to 85% MeCN in water over a 35 min period, where bothsolvents contain 0.1% TFA) provided the title compound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 10.94 (1 H, br s), 7.20-7.27 (3 H, m),7.13-7.18 (1 H, m), 7.09 (1 H, t, J=7.7 Hz), 6.85-6.95 (2 H, m), 6.66 (1H, d, J=7.6 Hz), 4.34 (1 H, d, J=10.2 Hz), 3.09 (1 H, d, J=14.8 Hz),2.87-3.01 (2 H, m), 2.68-2.77 (1 H, m), 2.25 (1 H, t, J=13.5 Hz),2.04-2.13 (1 H, m), 1.87-2.04 (2 H, m), 1.39-1.51 (2 H, m), 1.38 (3 H,s), 0.95 (3 H, t, J=7.4 Hz), 0.50 (3 H, t, J=7.4 Hz). Mass Spectrum(ESI) m/z=518 (M+1), 540 (M+23).

Example 85

3-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)methyl)-1,2,4-thiadiazol-5(4H)-one

The title compound was prepared by methods similar to those described inExample 84. ¹H NMR (400 MHz, CDCl₃) δ ppm 10.89 (1 H, br s), 7.24-7.30(2 H, m), 7.18-7.22 (m, 1 H), 7.15 (1 H, t, J=7.8 Hz), 7.04 (1 H, br s),6.86 (2 H, d, J=8.3 Hz), 6.77 (1 H, d, J=7.8 Hz), 4.53 (1 H, d, J=8.3Hz), 3.41-3.50 (1 H, m), 2.90-3.04 (3 H, m), 2.05-2.19 (2 H, m), 1.27 (6H, dd, J=6.6 Hz, 6.6 Hz), 1.23 (s, 3 H). Mass Spectrum (ESI) m/z=490(M+1), 512 (M+23).

Example 86

(3R,5R,6S)-3-((1H-Tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one

The title compound was prepared from2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 73) as described in Example 51.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.20 (s, 3H), 1.27 (d, J=6.9 Hz, 3H), 1.29(d, J=6.8 Hz, 3H), 2.20 (m, 2H), 3.08 (m, 1H), 3.41 (d, J=15.7 Hz, 1H),3.47 (m, 1H), 3.50 (d, J=15.6 Hz, 1H), 4.52 (d, J=8.8 Hz, 1H), 6.78 (m,3H), 7.06 (m, 1H), 7.16 (m, 1H), 7.23 (m, 3H). Mass spectrum (ESI) m/z458.0 [M+H]⁺.

Example 872-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid

Step A.(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(pentan-3-yl)piperidin-2-one

To a solution of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 42, Step A) (440 mg, 1.221 mmol) in 3-bromopentane (3196 μL,25.6 mmol) under nitrogen at rt was added a dispersion of 60% sodiumhydride in mineral oil (244 mg, 6.11 mmol). Evolution of gas wasobserved. The reaction was stirred at room temperature for 10 min andthen heated to 120° C. under N₂ for 19 h. The reaction mixture wascooled to room temperature and quenched with sat. NH₄Cl. The layers wereseparated and the organic layer was dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the titlecompound as a mixture of diastereomers.

Step B.(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(pentan-3-yl)piperidin-2-one

To(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(pentan-3-yl)piperidin-2-one(Example 87, Step A) (125 mg, 0.290 mmol) was added toluene (15 mL) andthe mixture was concentrated under reduced pressure. This step wasrepeated three times. Inhibitor free THF (1 mL) was added and themixture was cooled to −78° C. Freshly prepared LDA (1.0M in THF) (290μL, 0.290 mmol) was added and the reaction turned a golden-yellow color.The reaction was warmed to 0° C. for 30 min and the reaction colorturned orange. The reaction was cooled to −78° C. and ethyl iodide (281μL, 3.49 mmol) was added. The reaction mixture was warmed to 0° C. andstirred for 30 min. The reaction was quenched with sat. NH₄Cl, warmed toroom temperature, diluted with EtOAc and the layers were separated. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel(eluent: 0 to 10% EtOAc in hexanes) to give the title compound as a 1:1mixture of diastereomers.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-(pentan-3-yl)piperidin-2-one(Example 87, Step B) as described in Example 42, Step C. Purification byreversed phase preparatory HPLC (eluent: 0 to 100% MeCN+0.1% TFA inwater+0.1% TFA) provided the title compound as the first elutingdiastereomer.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.50 (3 H, t, J=7.5 Hz) 0.95 (3 H,t, J=7.5 Hz) 1.00 (3 H, t, J=7.5 Hz) 1.29-1.45 (2 H, m) 1.45-1.53 (1 H,m) 1.84-2.01 (4 H, m) 2.30 (1 H, t, J=13.8 Hz) 2.72-2.80 (2 H, m)3.03-3.11 (2 H, m) 4.34 (1 H, d, J=10.3 Hz) 6.69 (1 H, d, J=7.6 Hz) 6.95(2 H, br s) 7.05-7.20 (2 H, m) 7.08-7.17 (2 H, m) 7.22-7.25 (1 H, m).Mass Spectrum (ESI) m/z=476 [M+H]⁺.

Example 88(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfonylmethyl)-1-(pentan-3-yl)piperidin-2-one

Step A. (5R,6S)-methyl5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxopiperidine-3-carboxylate

LHMDS (5.42 mL, 5.42 mmol) was added to a solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one(Example 71, Step B) (1.75 g, 3.61 mmol) in anhydrous THF (14.45 mL) atrt under argon. After 5 minutes dimethyl dicarbonate (1.159 mL, 10.84mmol) was added. After 4 hours TLC indicated that a significant amountof product had formed but some starting material remained. AdditionalLHMDS (5.42 mL, 5.42 mmol) was added followed by dimethyl dicarbonate(1.159 mL, 10.84 mmol). After 2.5 hours the reaction was quenched by theaddition of sat. aq. NH₄Cl and the layers were separated. The aqueouslayer was extracted with EtOAc twice and the organics were pooled,washed with sat. aq. NaCl solution, dried (MgSO₄), filtered andconcentrated in vacuo to provide a yellow oil. Purification using a 120g SiO₂ column and eluting with 25 to 40% EtOAc/hexanes provided thetitle compound as a colorless oil as a mixture of isomers.

Step B.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-(hydroxymethyl)-3-methylpiperidin-2-one

2M lithium borohydride (1.078 mL, 2.157 mmol) was added to a solution of(5R,6S)-methyl5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxopiperidine-3-carboxylate(Example 88, Step A) (1.17 g, 2.157 mmol) in anhydrous THF (21.57 mL)and anhydrous ether (20 mL) at 0° C. under nitrogen. The reaction wasquenched after 58 hours with the addition of sat. aq. NH₄Cl and thelayers were separated. The aqueous layer was extracted with EtOAc twiceand the organics were pooled, washed with sat. aq. NaCl solution, dried(MgSO₄), filtered and concentrated in vacuo to provide a colorless oil.Purification using a 80 g SiO₂ column and eluting with 35 to 65%EtOAc/hexanes provided the title compound as a ˜30:1 mixture of isomers.

Step C.((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxopiperidin-3-yl)methyl4-methylbenzenesulfonate

DMAP (0.015 g, 0.120 mmol) was added to a solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-(hydroxymethyl)-3-methylpiperidin-2-one(Example 88, Step B) (0.616 g, 1.197 mmol) and tosyl-Cl (0.457 g, 2.395mmol) in pyridine (5.99 mL) at rt. The reaction mixture was heated at100° C. for 5 hours before removing the solvent in vacuo to provide abeige oil. Purification using a 80 g SiO₂ column and eluting with 25 to55% EtOAc/hexanes provided the title compound as a colorless oil as a33:1 mixture of isomers.

Step D.(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-3-(methylthiomethyl)piperidin-2-one

Sodium thiomethoxide (0.193 g, 2.76 mmol) was added to a solution of((5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-2-oxopiperidin-3-yl)methyl4-methylbenzenesulfonate (Example 88, Step C) (0.738 g, 1.104 mmol) inanhydrous DMF (5.52 mL) at rt under nitrogen. The reaction mixture washeated at 50° C. for 8 hours before being cooled to rt, diluted withwater and extracted with ether three times. The organics were pooled,washed with water three times, sat. aq. NaCl solution, dried (MgSO₄),filtered and concentrated in vacuo to provide a colorless oil.Purification using a 40 g SiO₂ column and eluting with 15 to 40%EtOAc/hexanes provided the title compound as a colorless foam.

Step E.(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylthiomethyl)piperidin-2-one

A solution of(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,4-dimethoxybenzyl)-3-methyl-3-(methylthiomethyl)piperidin-2-one(Example 88, Step D) (0.406 g, 0.746 mmol) in TFA (6.00 mL) was heatedat 50° C. under nitrogen for 2 hours. The reaction mixture wasconcentrated in vacuo to provide a purple oil. Purification using a 40 gSiO₂ column and eluting with 35 to 60% EtOAc/hexanes provided the titlecompound as a white solid.

Step F.(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylthiomethyl)-1-(pentan-3-yl)piperidin-2-one

NaH (0.076 g, 1.900 mmol) was added to a solution of(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylthiomethyl)piperidin-2-one(Example 88, step E) (0.150 g, 0.380 mmol) in 3-bromopentane (1.42 mL,11.41 mmol) at rt under nitrogen. The reaction mixture was heated at120° C. for 24 hours, cooled to rt, diluted with water and extractedwith DCM three times. The organics were pooled, washed with sat. aq.NaCl solution, dried (MgSO₄), filtered and concentrated in vacuo toprovide a yellow oil. Purification using a 24 g SiO₂ column and elutingwith 15% EtOAc/hexanes provided the title compound as a colorless syrup.

Step G.(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylsulfonylmethyl)-1-(pentan-3-yl)piperidin-2-one

3-Chloroperbenzoic acid (0.054 g, 0.242 mmol) was added to a solution of(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-3-(methylthiomethyl)-1-(pentan-3-yl)piperidin-2-one(Example 88, Step F) (0.045 g, 0.097 mmol) in DCM (0.969 mL) at 0° C.The reaction mixture was stirred at rt for 1 hour, washed with sat.NaHCO₃, sat. aq. NaCl solution, dried (MgSO₄), filtered and concentratedin vacuo to provide a colorless oil. Purification using a 4 g SiO₂ ISCOcolumn and eluting with 25 to 75% EtOAc/hexanes provided the titlecompound as a colorless glass.

¹H NMR (500 MHz, CDCl₃) δ ppm 0.49 (t, J=7.6 Hz, 3H), 0.95 (t, J=7.5 Hz,3H), 1.39 (m, 1H), 1.54 (s, 3H), 1.56 (m, 1H), 1.89 (m, 2H), 2.10 (m,1H), 2.57 (dd, J=14.4 and 3.1 Hz, 1H), 2.72 (m, 1H), 3.05 (s, 3H), 3.24(d, J=13.9 Hz, 1H), 3.63 (m, 1H), 3.82 (d, J=13.9 Hz, 1H), 4.40 (d,J=10.7 Hz, 1H), 6.78 (m, 1H), 7.02 (br s, 1H), 7.06 (m, 2H), 7.10 (m,2H), 7.20 (m, 2H). Mass spectrum (ESI) m/z 496.2 [M+H]⁺.

Example 892-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoicacid

LiOH (0.267 g, 11.13 mmol) in water (2.6 mL) was added to a solution ofmethyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(Example 65, Step B) (0.528 g, 1.113 mmol) in MeOH (7.5 mL) at rt. Thereaction mixture was heated at 80° C. for 14 hours, cooled to rt andacidified to pH=1 with 3M HCl. The mixture was extracted with EtOActhree times and the organics were pooled, washed with sat. aq. NaClsolution, dried (MgSO₄), filtered and concentrated in vacuo to provide awhite solid. Purification using a 40 g SiO₂ column and eluting with35-60% EtOAc/hexanes provided the title compound as a mixture ofisomers.

Step B.N′-(2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoyloxy)cyclopropanecarboximidamide

1,1′-Carbonyldiimidazole (0.104 g, 0.639 mmol) was added to a solutionof2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoicacid (Example 89, Step A) (0.196 g, 0.426 mmol) in dichloromethane(1.703 mL) at rt and stirred for 22 hours before addingn-hydroxycyclopropanecarboxamidine (0.064 g, 0.639 mmol). After 6 hoursthe reaction mixture was adsorbed onto silica and purified using a 12 gSiO₂ ISCO column and eluting with 35 to 60% EtOAc/hexanes to provide a2:1 mixture of isomers.

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one

A solution of tetrabutylammonium fluoride (1.0M in THF, 1.880 mL, 1.880mmol) was added to a solution ofN′-(2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoyloxy)cyclopropanecarboximidamide(Example 89, Step B) (0.204 g, 0.376 mmol) in THF (3.76 mL) at rt. After2 hours the reaction mixture was concentrated in vacuo and purifiedusing a 24 g SiO₂ column eluting with 25% Et₂O/hexames to provide(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one.

Further elution provided(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one(Example 89, Step C), as described in Example 42 Step C. Purificationusing a 4 g SiO₂ column and eluting with 35 to 100% EtOAc/hexanesprovided the title compound as a colorless film.

¹H NMR (500 MHz, CDCl₃) δ ppm 0.84 (t, J=7.5 Hz, 3H), 0.89 (m, 2 H),1.01 (m, 2H), 1.25 (m, 1H), 1.43 (s, 3H), 1.95 (m, 1H), 1.98 (m, 1H),2.20 (m, 2H), 2.37 (m, 1H), 2.90 (m, 2H), 3.26 (m, 1H), 4.60 (t, J=6.9Hz, 1H), 4.63 (d, J=10.3 Hz, 1H), 6.76 (m, 1H), 6.90 (m, 2H), 7.00 (brs, 1H), 7.10 (t, J=7.9 Hz, 1H), 7.16 (m, 3H). Mass spectrum (ESI) m/z542.2 [M+H]⁺.

Example 902-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(3-cyclopropyl-1,2,4-oxadiazol-5-yl)propyl)-3-methylpiperidin-2-one(Example 89, Step C) as described in Example 42, Step C.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.85-1.05 (m, 3H) 1.09 (t, J=7.6 Hz, 3H),1.44 (s, 3H), 2.01 (m, 1H), 2.19 (m, 1H), 2.26 (m, 3H), 2.83 (d, J=14.7Hz, 1H), 2.91 (d, J=14.7 Hz, 2H), 3.32 (m, 1H), 3.95 (t, J=7.2 Hz, 1H),4.57 (d, J=10.4 Hz, 1H), 6.73 (m, 1H), 6.98 (m, 1H), 7.09 (t, J=7.8 Hz,1H), 7.16 (m, 2H), 7.20 (m, 3H). Mass spectrum (ESI) m/z 542.2 [M+H]⁺.

Example 912-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A. (S)-Methyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) (4.00 g, 10.7 mmol) in 45 mL of DMF was added adispersion of 60% sodium hydride in mineral oil (1.71 g, 42.7 mmol) at0° C. After being stirred for 20 min, methyl 2-bromobutanoate (6.15 mL,53.4 mmol) was added at 0° C. and the resulting solution was stirred at25° C. for 12 h until completion of the reaction. Then sat. aq. NH₄Clsolution was added and the mixture was extracted with ethyl acetate. Thecombined organic layers were washed with water and sat. aq. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. Purification of the residue by flashchromatography on silica gel (eluent: 0 to 100% MTBE/hexanes, gradientelution), followed by separation of individual stereoisomers by chiralSFC (flowrate: 65 mL/min on a ChiralPak ®AD-H column (Diacel Inc., FortLee, N.J.) using 3:1 heptanes/IPA (0.1% DEA)/CO₂ as the eluent) providedthe title compound as the faster eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J=8.4 Hz), 7.06-7.17(2 H, m), 7.00 (3 H, t, J=1.8 Hz), 6.77 (1 H, d, J=7.6 Hz), 5.79-5.94 (1H, m), 5.20 (1 H, d, J=4.7 Hz), 5.17 (1 H, s), 4.56 (1 H, d, J=10.8 Hz),3.73 (3 H, s), 3.25-3.37 (1 H, m), 3.18 (1 H, dd, J=7.6 Hz, 4.9 Hz),2.61 (2 H, d, J=7.4 Hz), 2.20-2.34 (1 H, m), 2.09-2.19 (1 H, m), 1.99 (1H, d, J=3.1 Hz), 1.57-1.72 (1 H, m), 1.24 (3 H, s), 0.61 (3H, t, J=7.5Hz); Mass Spectrum (ESI) m/z=474.1 [M+H]⁺.

Further elution provided:

(R)-Methyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

as the slower eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (2 H, d, J=8.0 Hz), 6.99-7.19(4 H, m), 6.95 (1 H, t, J=1.8 Hz), 6.71 (1 H, d, J=7.6 Hz), 5.81-5.95 (1H, m), 5.19 (1 H, d, J=2.7 Hz), 5.16 (1 H, d, J=1.0 Hz), 4.48 (1 H, d,J=10.6 Hz), 3.67 (3 H, s), 3.24-3.32 (1 H, m), 3.20 (1 H, dd, J=7.8 Hz,6.1 Hz), 2.61-2.72 (1 H, m), 2.49-2.60 (1 H, m), 1.91-2.21 (4 H, m),1.27 (3 H, s), 1.00 (3 H, t, J=7.5 Hz); MS (ESI) m/z=474.1 [M+H]⁺.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

To a solution of (S)-methyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoateand (R)-methyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(1.73 g, 3.64 mmol) (mixture of stereoisomers from Example 91, Step A)in 27 mL of Et₂O and 9 mL of THF was added a solution of lithiumtetrahydroborate in THF (0.238 mL, 7.28 mmol) at 0° C. The resultingsolution was stirred at 25° C. for 2 h. The reaction was quenched (10%citric acid), extracted (2×EtOAc) and washed (1×Sat. aq. NaCl solution).The combined organic layers were washed with sat. aq. NaCl solution,dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. The residue was purified by flash chromatography onsilica gel (eluent: 0-60% EtOAc in hexanes) to give the title compoundas the faster eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (t, J=7.4 Hz, 3 H), 1.29 (s, 3H), 1.79-2.03 (m, 4 H), 2.62 (d, J=7.4 Hz, 2 H), 2.80-2.85 (m, 1 H),3.05-3.16 (m, 1 H), 3.40-3.49 (m, 2 H), 4.33 (d, J=10.4 Hz, 1 H),5.13-5.22 (m, 2 H), 5.79-5.95 (m, 1 H), 6.7 (d, J=7.6 Hz, 1 H),6.85-6.97 (m, 3 H), 7.08-7.15 (m, 1 H), 7.17-7.19 (m, 1 H), 7.23 (d,J=8.6 Hz, 2 H); Mass Spectrum (ESI) m/z=446 (M+1).

Further elution provided:

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

as the slower eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.68 (t, J=7.5 Hz, 3 H), 1.27 (s, 3H), 1.38-1.52 (m, 1 H), 1.90-2.08 (m, 4 H), 2.61 (d, J=7.4 Hz, 2 H),3.10-3.25 (m, 2 H), 3.59-3.68 (m, 2 H), 4.46 (d, J=10.2 Hz, 1 H), 5.18(dd, J=13.7, 1.8 Hz, 2 H), 5.79-5.93 (m, 1 H), 6.72 (d, J=7.6 Hz, 1 H),6.93-7.04 (m, 2 H), 7.09-7.13 (m, 1 H), 7.15-7.20 (m, 1 H), 7.24 (d,J=8.6 Hz, 2 H); Mass Spectrum (ESI) m/z=446 (M+1).

Step C.(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal

To a solution of 218 mg (0.49 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 91, Step B) in a mixture of water (13.20 μL, 0.733 mmol) andDCM (4883 μL) was added1,1,1,-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)one (“Dess Martinperiodinane”) (311 mg, 0.733 mmol) at ambient temperature. The reactionwas monitored by LCMS, and several small portions of additionalperiodinane were added until the reaction was complete. The reaction wasquenched (2 mL, 1 M Na₂S₂O₃), extracted (2×DCM), and the combinedorganic layers were washed with sat. NaHCO₃ solution (2×), sat NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. Purification of the residue by flashchromatography on silica gel (eluent: 20 to 35% EtOAc/hexanes, gradientelution) provided the title compound.

Step D.(3S,5R,6S)-3Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one

To a solution of 100 mg (0.225 mmol) of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 91, Step C) in DCE (2420 μL) was added morpholine (200 μL,2.297 mmol), acetic acid (1.288 μL, 0.023 mmol) and sodiumtriacetoxyborohydride (95 mg, 0.450 mmol). The reaction mixture wasstirred at room temperature for 18 hours. The reaction was quenched withsat. sodium bicarbonate solution and extracted with DCM (2×10 mL). Thecombined organic layers were washed with sat NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure to afford the crude title compound as an oil.

Step E.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde

To a round-bottomed flask charged with(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one(Example 91, Step D) (125 mg, 0.242 mmol) was added THF (2 mL).Approximately 1 mL water was added dropwise until the solution becameand remained cloudy with gentle stirring. t-BuOH (0.350 mL) was addeddropwise until the solution became homogeneous. NMO (42.6 mg, 0.364mmol) was added followed by osmium tetroxide, 4 wt. %, in water (1 dropfrom glass Pasteur pipette). The reaction mixture was stirred at roomtemperature for 16 hours. An additional drop of osmium tetroxide, 4 wt.%, in water was added. After 5 hours, two additional drops of osmiumtetroxide, 4 wt. %, in water were added and the reaction mixture wasstirred at room temperature for an additional 16 hours. Sodium periodate(145 mg, 0.679 mmol) was added and the reaction mixture was stirred atroom temperature for 2 hours. The reaction mixture was diluted withethyl acetate (10 mL) and water (10 mL) and filtered. The aqueous layerof the filtrate was extracted with additional ethyl acetate (10 mL) andthe combined organic layers were washed with sat. aq. NaCl solution,dried over sodium sulfate, filtered and the filtrate was concentratedunder reduced pressure to provide the title compound.

Step F.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde(Example 91, Step E) (125 mg, 0.242 mmol) in acetone (2 mL) was added 3mL of a mixture of CrO₃ in water (2 mL) and concentrated H₂SO₄ (1 ml).The reaction mixture was stirred at room temperature for 2 hours andthen diluted with water (10 mL) and ethyl acetate (10 mL) and the layerswere separated.

The aqueous layer was extracted with additional ethyl acetate (10 mL).The combined organic layers were concentrated under reduced pressure.The residue was purified by reversed phase preparatory HPLC (column:Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to100% MeCN+0.1% TFA in water+0.1% TFA) to provide the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.57 (t, J=7.53 Hz, 1 H) 1.26 (s, 1H) 1.39 (s, 3 H) 1.54-1.70 (m, 1 H) 1.72-1.89 (m, 1 H) 2.02-2.27 (m, 3H) 2.49 (br. s., 2 H) 2.69 (br. s., 2 H) 2.82 (m, 2 H) 3.02 (br. s., 2H) 3.13-3.30 (m, 2 H) 3.74-3.93 (m, 4 H) 4.47-4.72 (m, 1 H) 6.75 (d,J=7.82 Hz, 1 H) 6.96 (t, J=1.86 Hz, 1 H) 7.01 (br. s., 1 H) 7.04-7.17(m, 3 H) 7.22 (d, J=8.41 Hz, 2 H). Mass Spectrum (ESI) m/z=533 [M+H]⁺.

Examples 92-94 were prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)piperidin-2-oneby procedures similar to those described in Example 91, substitutingmorpholine in step D for the appropriate amount of amine

Example R = 92

93

94

Example 922-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.56 (t, J=7.43 Hz, 3 H) 1.23-1.35(m, 1 H) 1.44 (s, 3 H) 1.48-1.65 (m, 2 H) 1.77-1.91 (m, 1 H) 2.02-2.11(m, 1 H) 2.13-2.25 (m, 1 H) 2.59-2.71 (m, 1 H) 2.73-2.84 (m, 1 H)2.90-3.24 (m, 5 H) 4.60 (d, J=10.17 Hz, 1 H) 6.69-6.77 (m, 1 H)6.91-7.05 (m, 3 H) 7.06-7.13 (m, 1 H) 7.13-7.18 (m, 1 H) 7.23 (d, J=8.22Hz, 2 H). Mass Spectrum (ESI) m/z=545 [M+H]⁺.

Example 932-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2,2-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.49 (t, J=7.34 Hz, 3 H) 1.21-1.30(m, 4 H) 1.34 (s, 3 H) 1.37 (s, 3 H) 1.42 (s, 3 H) 1.51-1.68 (m, 1 H)1.86 (dd, J=14.48 and 7.24 Hz, 1 H) 2.08-2.22 (m, 2 H) 2.30 (br. s., 1H) 2.35-2.48 (m, 2 H) 2.74-2.84 (m, 1 H) 2.86-2.94 (m, 1 H) 3.00-3.22(m, 2 H) 3.68-3.91 (m, 2 H) 4.57 (d, J=10.37 Hz, 1 H) 6.68 (d, J=7.63Hz, 1 H) 6.91-7.00 (m, 2 H) 7.03-7.11 (m, 1 H) 7.14 (d, J=7.24 Hz, 2 H)7.23 (d, J=7.43 Hz, 2 H). Mass Spectrum (ESI) m/z=561 [M+H]⁺.

Example 942-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-(2,6-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The crude product was purified by reversed phase preparatory HPLC(column: Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.;eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA) to provide a 4:1ratio of diastereomers of undetermined configuration at the positionsindicated by *.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.02 (br. s., 1 H) 1.24 (d, J=6.06Hz, 6 H) 1.35-1.49 (m, 4 H) 2.02-2.44 (m, 4 H) 2.68 (s, 1 H) 2.79-2.89(m, 2 H) 3.20-3.32 (m, 2 H) 3.37-3.49 (m, 1 H) 3.80-4.00 (m, 2 H) 4.10(br. s., 3 H) 4.23-4.34 (m, 1 H) 4.41-4.58 (m, 1 H) 4.91-5.10 (m, 1 H)6.89-6.98 (m, 2 H) 6.99-7.15 (m, 4 H) 7.20-7.30 (m, 2 H). Mass Spectrum(ESI) m/z=561 [M+H]⁺.

Example 952-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. tert-butyl4-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)piperazine-1-carboxylate

The title compound was prepared from(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 91, Step C) and tert-butyl piperazine-1-carboxylate accordingto the procedure described in Example 91 Step D.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one

To a solution of tert-butyl4-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)piperazine-1-carboxylate(Example 95, Step A) (187 mg, 0.304 mmol in DCM (2.4 mL) was added TFA(600 μL, 7.79 mmol). The reaction mixture was stirred at roomtemperature for 16 hours before concentrating under reduced pressure.The residue was taken up in DCM (15 mL) and washed with sat. sodiumbicarbonate solution (10 mL) and saturated sodium chloride solution (10mL). The organic layer was dried over sodium sulfate, filtered and thefiltrate concentrated under reduced pressure to afford the titlecompound as a white foam.

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one(Example 95, Step B) (60 mg, 0.117 mmol) in DCE (1.2 mL) was addedcyclopropanesulfonyl chloride (23.76 μL, 0.233 mmol) followed bydiisopropylethylamine (40.6 μL, 0.233 mmol). The reaction mixture wasstirred at room temperature for 16 hours, diluted with water (10 mL) andthe layers were separated. The aqueous layer was extracted with DCM(2×10 mL). The combined organic layers were washed with saturated NaClsolution (10 mL), dried over sodium sulfate, filtered, and the filtrateconcentrated under reduced pressure to afford the title compound as asolid.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a 10 mL round-bottomed flask charged with(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopropylsulfonyl)piperazin-1-yl)butan-2-yl)-3-methylpiperidin-2-one(Example 23, Step C) (85.1 mg, 0.138 mmol) was added THF (˜800 uL)followed by water (˜600 uL, until the reaction remains cloudy withgentle stirring) followed by tBuOH (˜200 uL, until the reaction becomestranslucent). NMO (24.17 mg, 0.206 mmol) was added followed by 5 dropsof osmium tetroxide, 4 wt. %, in water (33.6 μL, 0.138 mmol) via pasteurpipette. The reaction was stirred at rt over night before adding Jonesreagent (0.154 mL). The reaction was stirred at room temperature for 2hours, diluted with water (15 mL) and extracted with ethyl acetate (3×15mL). The combined organic layers are washed with water (3×20 mL),saturated sodium chloride solution (20 mL), dried over sodium sulfate,filtered and the filtrate concentrated under reduced pressure. Theresidue was purified by reversed phase preparatory HPLC (column:Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.92-1.25 (m, 10 H) 1.43 (s, 3 H)1.85 (br. s., 1 H) 2.08 (d, J=13.50 Hz, 1 H) 2.16-2.30 (m, 1 H) 2.40 (d,J=5.87 Hz, 2 H) 2.52 (br. s., 2 H) 2.69-2.79 (m, 2 H) 2.79-2.92 (m, 2 H)3.21-3.34 (m, 2 H) 3.83 (br. s., 3 H) 4.51 (br. s., 1 H) 6.67 (br. s., 1H) 6.91-7.01 (m, 2 H) 7.03-7.09 (m, 2 H) 7.11-7.18 (m, 3 H). MassSpectrum (ESI) m/z=636 [M+H]⁺.

Example 962-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4-(methylsulfonyl)piperazin-1-yl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one(Example 95, Step B) and methanesulfonyl chloride as described inExample 95, Steps C and D.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (br. s., 3 H) 1.42 (s, 3 H)1.85 (br. s., 2 H) 2.00-2.13 (m, 1 H) 2.14-2.28 (m, 1 H) 2.56 (br. s.,3H) 2.66-2.77 (m, 3 H) 2.85 (d, J=14.48 Hz, 2 H) 2.90-2.99 (m, 3 H) 3.27(t, J=10.27 Hz, 3 H) 3.80 (br. s., 3 H) 4.51 (br. s., 1 H) 6.63-6.71 (m,1 H) 6.97 (s, 2 H) 7.03-7.10 (m, 2 H) 7.11-7.17 (m, 3 H). Mass Spectrum(ESI) m/z=610 [M+H]⁺.

Example 972-((3R,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one(Example 95, Step B) (80 mg, 0.155 mmol) in DCE (1.5 mL) was addedacetyl chloride (22.1 μL, 0.31 mmol) followed by diisopropylethylamine(54.1 μL, 0.311 mmol). The reaction mixture was stirred at roomtemperature for 16 hours and then concentrated under reduced pressure toprovide the title compound.

Step B.2-((3R,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-1-((S)-1-(4-acetylpiperazin-1-yl)butan-2-yl)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 97, Step A) as described in Example 95, Step D. The residue waspurified by reversed phase preparatory HPLC (column: Gemini-NX C₁₈ 5 umcolumn; Phenomonex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA inwater+0.1% TFA, over 20 minutes) to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.94-1.18 (m, 3 H) 1.42 (s, 3 H)1.77-1.98 (m, 1 H) 2.12 (s, 4 H) 2.23 (s, 2 H) 2.48-2.63 (m, 3 H) 2.67(s, 3 H) 2.84 (br. s., 3 H) 3.16-3.35 (m, 2 H) 3.83-4.05 (m, 3 H)4.43-4.61 (m, 1 H) 6.62-6.75 (m, 1 H) 6.97 (s, 2 H) 7.07 (d, J=7.83 Hz,2 H) 7.10-7.17 (m, 3 H). Mass Spectrum (ESI) m/z=574 [M+H]⁺.

Example 982-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-(cyclopropanecarbonyl)piperazin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(piperazin-1-yl)butan-2-yl)piperidin-2-one(Example 95, Step B) and cyclopropanecarbonyl chloride as described inExample 97.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.79-0.91 (m, 6 H) 1.02 (br. s., 6H) 1.43 (s, 3 H) 1.65-1.75 (m, 2 H) 2.11 (br. s., 2 H) 2.17-2.30 (m, 2H) 2.51 (br. s., 3 H) 2.65 (s, 2 H) 2.80-2.88 (m, 2 H) 3.29 (t, J=11.44Hz, 2 H) 6.98 (s, 2 H) 7.06 (t, J=7.83 Hz, 2 H) 7.10-7.16 (m, 2 H)7.19-7.26 (m, 2 H). Mass Spectrum (ESI) m/z=600 [M+H]⁺.

Example 993-(((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)methyl)-1,2,4-oxadiazol-5(4H)-one

The title compound was prepared from2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid (Example 91) using a similar procedure as the one described forExample 82. The crude product was purified by flash chromatography onsilica gel (eluent: 0 to 10% MeOH in DCM) to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.56 (t, J=7.34 Hz, 3 H) 1.29 (br.s., 1 H) 1.30-1.38 (m, 3 H) 1.57 (ddd, J=13.99, 7.53 and 3.91 Hz, 1 H)1.81 (dt, J=14.48 and 7.43 Hz, 1 H) 2.09 (dd, J=13.99 and 3.03 Hz, 1 H)2.18 (d, J=9.98 Hz, 1 H) 2.22-2.32 (m, 1 H) 2.46 (d, J=3.72 Hz, 2 H)2.66 (br. s., 2 H) 2.90 (d, J=15.06 Hz, 1 H) 2.95-3.21 (m, 4 H)3.74-3.89 (m, 4 H) 4.59 (d, J=10.17 Hz, 1 H) 6.72 (d, J=7.63 Hz, 1 H)6.84-6.99 (m, 3 H) 7.08-7.13 (m, 1 H) 7.14-7.18 (m, 1 H) 7.23 (d, J=8.22Hz, 2 H). Mass Spectrum (ESI) m/z=573 [M+H]⁺.

Example 1002-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5,5-dimethyl-2-oxooxazolidin-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropylamino)butan-2-yl)-3-methylpiperidin-2-one

The title compound was prepared as described in Example 91, Step D andusing and using 1-amino-2-methylpropan-2-ol (Tyger Scientific, Inc.,Ewing, N.J.).

Step B.3-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-5,5-dimethyloxazolidin-2-one

To a solution of 42 mg (0.081 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-hydroxy-2-methylpropylamino)butan-2-yl)-3-methylpiperidin-2-one(Example 100, Step A) in dioxane (2705 μL) was added carbonyldiimidazole(132 mg, 0.812 mmol). The reaction was heated to 100° for 6 h.Purification of the residue by reversed phase HPLC (Sunfire™ Prep C₁₈OBD 10 μm column (Waters, Milford, Mass.) (eluent: 60 to 85% MeCN/water(0.1% TFA), gradient elution) provided the title compound.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(5,5-dimethyl-2-oxooxazolidin-3-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid.

To a rapidly stirring solution of 20 mg (0.037 mmol) of3-((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-5,5-dimethyloxazolidin-2-one(Example 100, Step B) in a mixture of CCl4 (210 μL), MeCN (210 μL), andwater (315 μL) was added sodium periodate (31.5 mg, 0.147 mmol),followed by catalytic ruthenium(III) chloride hydrate (4.15 mg, 0.018mmol). When complete by LCMS monitoring, acidified the reaction withcitric acid and diluted with chloroform. Insoluble material was removedby filtration through celite. Extracted to ethyl acetate and thecombined organic layer was washed with sat. NaCl, dried over Na₂SO₄,filtered and the filtrate was concentrated in vacuo. Purification of theresidue by reversed phase HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column(Waters, Milford, Mass.) (eluent: 60 to 80% MeCN/water (0.1% TFA),gradient elution) provided the title compound as a white powder.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J=7.21 Hz, 2 H) 0.94 (br.s., 2 H) 1.27 (d, J=2.93 Hz, 1 H) 1.33 (d, J=2.69 Hz, 1 H) 1.52 (t, 7 H)1.88-1.99 (m, 2 H) 2.34 (t, J=13.82 Hz, 1 H) 2.71 (d, J=14.92 Hz, 2 H)2.95-3.12 (m, 4 H) 3.29-3.39 (m, 2 H) 4.44 (d, J=10.27 Hz, 1 H) 6.73 (d,J=7.58 Hz, 1 H) 6.95 (s, 2 H) 7.11 (t, J=7.70 Hz, 1 H) 7.13-7.20 (m, 1H). Mass Spectrum (ESI) m/z=561 (M+1).

Example 1012-((3R,5R,6S)-1-((S)-1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoicacid

To a 15-mL round-bottomed flask was added (S)-tert-butyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(420 mg, 0.813 mmol) (Example 1, Step F) and anisole (444 μL, 4.07mmol), followed by TFA (4066 μL) which had been pre-cooled to 0° C. Thereaction mixture was stirred at 0° C. for 1 h, diluted with 50 ml ofether, and the combined organics were washed with 20 ml water,NaHCO₃/sat NaCl solution until neutral, then dried over Na₂SO₄, filteredand the filtrate was concentrated. Purification of the residue by flashchromatography on silica gel (eluent: 0 to 20% EtOAc/hexanes, gradientelution) provided the title compound.

1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (1 H, s), 7.07-7.19 (2 H, m),7.00 (3 H, br. s.), 6.76 (1 H, d, J=7.4 Hz), 5.77-5.93 (1 H, m),5.15-5.25 (2 H, m), 4.58 (1 H, d, J=10.8 Hz), 3.35 (1 H, br. s.),3.23-3.33 (1 H, m), 2.62 (2 H, d, J=7.2 Hz), 2.27 (1 H, dquin, J=14.6,7.5, 7.5, 7.5, 7.5 Hz), 2.14 (1 H, t, J=13.5 Hz), 1.99 (1 H, dd, J=13.7,2.9 Hz), 1.50-1.64 (1 H, m), 1.29 (3 H, s), 0.66 (3 H, t, J=7.4 Hz).

Step B.2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-tert-butylbutanamide

To a solution of2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoicacid (81 mg, 0.176 mmol) (Example 101, Step A) in dry DMF (880 μL) with3 eq TEA (73.6 μL, 0.528 mmol) at 0° was added 2 eq HATU (134 mg, 0.352mmol). The reaction was stirred at 0° for 5 min, followed by addition oft-butyl amine (25.7 mg, 0.352 mmol). It was stirred for 30 min at 0°,quenched with sat. NaHCO₃ and extracted to EtOAc. The combined organiclayers were washed with sat. NaCl solution, dried over Na₂SO₄, filteredand the filtrate was concentrated. Purification of the residue by flashchromatography on silica gel (eluent: 0-30% EtOAc/hexanes, gradientelution) provided the title compound as a mixture of stereoisomers.

Step C.2-((3R,5R,6S)-1-((S)-1-(tert-butylamino)-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one(Example 101, Step B) as described in Example 1, Step H. The crudeproduct was purified by reversed phase preparatory HPLC (Sunfire™ PrepC₁₈ OBD 10 μm column (Waters, Milford, Mass.) (eluent: 55% acetonitrile,water, 0.1% TFA, gradient elution).

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.71 (t, J=7.46 Hz, 3 H), 1.32 (s,9 H), 1.40 (s, 3 H), 1.60-1.71 (m, 1 H), 2.07-2.25 (m, 3 H), 2.86 (d,J=2.20 Hz, 2 H), 3.16 (ddd, J=12.65, 9.60, 3.42 Hz, 1 H), 3.67 (dd,J=8.80, 5.62 Hz, 1 H), 4.70 (d, J=9.78 Hz, 1 H), 6.78 (d, J=7.58 Hz, 1H), 6.97 (s, 1 H), 6.98-7.05 (m, 3 H), 7.11 (t, J=7.83 Hz, 1 H),7.14-7.19 (m, 1 H), 7.21 (d, J=8.56 Hz, 2 H). Mass Spectrum (ESI)m/z=533 (M+1).

Example 1022-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S,3R)-2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methylpiperidin-2-one

To a solution of 4 g (10.69 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) in 100 mL of THF was added water (60 mL) followedby 4-methylmorpholine 4-oxide (1.878 g, 16.03 mmol). The cloudy reactionmixture became clear within 5 min and osmium(VIII) oxide (4% aq) (0.340mL, 0.053 mmol) was added and the reaction mixture remained clear. Thereaction mixture was stirred at room temperature for 18 h. Osmium(VIII)oxide (4% aq) (0.1 mL) was added and the reaction mixture was stirred atroom temperature for 24 h. Sat NaCl solution was added and the mixturewas extracted with EtOAc. The organic layers were combined, dried overNa₂SO₄, filtered and the filtrate was concentrated to give the titlecompound as a 1:1 ratio of diastereomers.

Step B.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one

To a solution of(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methylpiperidin-2-one(Example 102, Step A) (4.900 g, 12.00 mmol) and 2,2-dimethoxypropane(14.76 mL, 120 mmol) in N,N-dimethylformamide (34 mL) at roomtemperature was added CSA (0.279 g, 1.200 mmol) and the reaction mixturewas allowed to stir for 1 hr at room temperature. The reaction wasquenched with sodium bicarbonate (100 mL) and EtOAc (100 mL). The layerswere separated and the organic layer was washed three times with sat.sodium carbonate (100 mL). The aqueous layers were combined and wereextracted with EtOAc (200 mL). The organic layers were combined, washedwith sat. aq. NaCl solution, dried with sodium sulfate, filtered, andconcentrated under reduced pressure to provide the title compound.

Step C.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one

To(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one(Example 102, Step B) (0.909 g, 2.027 mmol) was added toluene (15 mL)and the mixture was concentrated under reduced pressure. This step wasrepeated three times. Inhibitor free THF (20 mL) was added and thesolution was cooled to −78° C. Butyllithium in pentane (2.0M) (1.014 mL,2.027 mmol) was added dropwise and the reaction mixture remainedcolorless. The reaction mixture warmed to 0° C. and the reaction colorturned very light yellow. nBuLi in pentane (2.0M) was added dropwiseuntil the reaction mixture remained bright yellow. The reaction mixturewas cooled to −78° C. and freshly prepared 3-bromocyclopent-1-ene (0.4g, 2.72 mmol) in THF (2 mL) was added dropwise. The reaction mixture waswrapped in foil and warmed to 0° C. The reaction mixture was stirred at0° C. for 1 h and then at rt for 2 days. The reaction was quenched withsat. NH₄Cl and extracted with EtOAc. The organic layer was dried overNa₂SO₄ and concentrated under reduced pressure. The residue was purifiedby flash chromatography on silica gel (eluent: 0 to 100% EtOAc inhexanes) to give the title compound as a colorless film.

Step D.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-(2,3-dihydroxypropyl)-3-methylpiperidin-2-one

To a solution of(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methylpiperidin-2-one(Example 28, Step C) (310 mg, 0.603 mmol) in THF (3 mL) at roomtemperature was added aq. HCl (1 M) (3013 μL, 3.01 mmol). The reactionmixture was stirred at room temperature for 19 h. The reaction mixturewas diluted with EtOAc and the layers were separated. The organic layerwas washed with sat. NaHCO₃, sat. aq. NaCl solution and dried overNa₂SO₄ and concentrated under reduced pressure to provide the titlecompound.

Step E.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde

To a solution of(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-(2,3-dihydroxypropyl)-3-methylpiperidin-2-one(Example 102, Step D) (286 mg, 0.603 mmol) in THF (3 mL) and water (3mL) was added sodium periodate (258 mg, 1.206 mmol) at room temperature.The slurry was stirred at room temperature for 1 h and then diluted withEtOAc and the layers were separated. The organic layer was washed withsat. Na₂S₂O₃ and sat. aq. NaCl solution and dried over Na₂SO₄ andconcentrated under reduced pressure to provide the title compound.

Step F.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde(Example 102, Step E) (267 mg, 0.604 mmol) in acetone (4 mL) was addedfreshly prepared Jones reagent (0.5 mL) at rt. The reaction mixture wasstirred at room temperature for 15 min. before it was diluted with EtOAcand washed with water and sat. aq. NaCl solution. The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (eluent: 50 to 100%EtOAc in hexanes) to give the title compound as a colorless film as a3.6:1 mixture of diastereomers.

Step G.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S,3R)-2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 102, Step F) (94 mg, 0.205 mmol) in THF (1.0 mL) was addedwater (0.25 mL) and tBuOH (0.2 mL) at room temperature. NMO (36.0 mg,0.308 mmol) was added followed by osmium tetroxide (4% aq) (1.303 μL,0.205 mmol). The reaction mixture was stirred at room temperature for 24h. Water (10 mL) was added and the mixture was extracted with DCM twice.The organic layers were combined and dried over Na₂SO₄ and concentratedunder reduced pressure. The residue, containing a mixture of threestereoisomers, was purified by reversed phase preparatory HPLC (column:Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.; eluent: 30 to50% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to provide thetitle compound as the first eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21-1.36 (3 H, m), 1.38 (3 H, s),1.53-1.56 (2 H, m), 2.20-2.02 (3 H, m), 2.22 (1 H, t, J=13.2 Hz),2.62-2.78 (1 H, m), 2.85-3.00 (1 H, m), 3.00-3.13 (1 H, m), 4.06-4.17 (1H, m), 4.35 (1 H, br s), 4.70 (1 H, d, J=8.8 Hz), 6.76-6.88 (1 H, m),6.93-7.12 (4 H, m), 7.12-7.25 (3 H, m). Mass Spectrum (ESI) m/z=492[M+H]⁺.

Further elution provided as the last eluting isomer Example 103.

Example 1032-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2R,3S)-2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.19-1.38 (1 H, m) 1.38-1.50 (3 H,m) 1.38-1.50 (1 H, m) 1.71-1.98 (2 H, m) 2.06-2.27 (3 H, m) 2.33 (1 H,d, J=8.2 Hz) 2.70-2.79 (1 H, m) 2.79-2.90 (1 H, m) 3.20-3.37 (2 H, m)3.40 (1 H, d, J=5.1 Hz) 3.86 (1 H, br. s.) 4.50 (1 H, d, J=10.2 Hz)6.67-6.77 (1 H, m) 6.93-7.07 (1 H, m) 7.06-7.19 (3 H, m) 7.23 (3 H, d,J=8.6 Hz). Mass Spectrum (ESI) m/z=492 [M+H]⁺.

Example 1042-((3R,3′S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)aceticacid or2-((3R,3′R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)aceticacid

Step A.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,5-dioxopentan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2,3-dihydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 102, Step F) (110 mg, 0.223 mmol) in THF (3 mL) and water(3 mL) was added sodium periodate (134 mg, 0.626 mmol) at roomtemperature. The reaction mixture was stirred at room temperature for 45min and was diluted with EtOAc and the layers were separated. Theorganic layer was washed with sat. aq. Na₂S₂O₃ solution, sat. aq. NaClsolution, dried over Na₂SO₄ and concentrated under reduced pressure toprovide the title compound.

Step B.2-((3R,3′S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)aceticacid or2-((3R,3′R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)aceticacid (Isomer 1)

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,5-dioxopentan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 104, Step A) (55 mg, 0.112 mmol) in DCE (1 mL) was added2,2,2-trifluoroethanamine (9.24 μL, 0.118 mmol) and sodiumtriacetoxyborohydride (76 mg, 0.359 mmol) at room temperature. Thecloudy reaction mixture was stirred at room temperature for 2 h. Thereaction mixture was concentrated under reduced pressure, diluted withDCM and washed with sat. aq. NaHCO₃ solution and sat. aq. NaCl solution.The layers were separated and the aqueous layer was extracted threetimes with DCM. The organic layers were combined, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byreversed phase preparatory HPLC (column: Gemini-NX C₁₈ 5 um column;Phenomonex, Torrance, Calif.; eluent: 40% MeCN+0.1% TFA in water+0.1%TFA, over 20 minutes) and concentrated in vacuo to provide the firsteluting diastereomer. The residue was dissolved in DCM (1 mL) and HCl inether (1M) (1 mL) was added and the solvent was removed under reducedpressure to provide the hydrochloride salt of one of the title compoundsas the first eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.73-1.00 (4 H, m), 1.13-1.53 (6 H,m), 1.58-1.84 (2 H, m), 1.98-2.13 (1 H, m), 2.24-2.44 (1 H, m),2.67-2.99 (3 H, m), 3.17-3.32 (1 H, m), 4.22 (2 H, t, J=6.0 Hz),6.65-6.91 (1 H, m), 7.00 (1 H, d, J=0.6 Hz), 7.05-7.24 (4 H, m),7.48-7.59 (1 H, m), 7.63-7.79 (1 H, m). Mass Spectrum (ESI) m/z=557[M+H]⁺.

Further elution and concentration in vacuo provided example 105.

Example 1052-((3R,3′S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)aceticacid or2-((3R,3′R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1′-(2,2,2-trifluoroethyl)-1,3′-bipiperidin-3-yl)aceticacid (Isomer 2)

The residue was dissolved in DCM (1 mL) and HCl in ether (1M) (1 mL) wasadded and the solvent was removed under reduced pressure to provide thehydrochloride salt of one of the title compounds as the second elutingisomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.73-1.08 (7 H, m), 1.13-1.50 (7 H,m), 1.69 (6 H, d, J=6.1 Hz), 7.54 (4 H, dd, J=5.7 and 3.3 Hz), 7.72 (4H, dd, J=5.7 and 3.3 Hz). Mass Spectrum (ESI) m/z=557 [M+H]⁺.

Example 1062-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3S)-3-hydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3R)-3-hydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)piperidin-2-one

To a solution of 3.25 g (10.16 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1,Step E) in DMF (150 mL) at 0° C. was added a dispersion of 60% sodiumhydride in mineral oil (1.016 g, 25.4 mmol). Evolution of gas wasobserved. The cloudy reaction mixture was stirred at 0° C. for 20 minbefore adding 3-bromocyclopent-1-ene (4.48 g, 30.5 mmol). The cloudyreaction mixture warmed to room temperature and stirred at roomtemperature for 18 h. The reaction was quenched with sat. aq. NH₄Clsolution, diluted with EtOAc and the layers were separated. The organiclayer was washed with 1M LiCl, sat. aq. NaCl solution, dried over Na₂SO₄and concentrated under reduced pressure. The residue was purified byflash chromatography on silica gel (eluent: 25 to 100% EtOAc in hexanes)to give the title compound as a 5:2 mixture of diastereomers.

Step B.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3-hydroxycyclopentyl)piperidin-2-one

To a solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)piperidin-2-one(Example 106, Step A) (394 mg, 1.020 mmol) in THF (10 mL) was addedborane tetrahydrofuran complex (1.0 m in THF) (1020 μL, 1.020 mmol).Evolution of gas was observed. The reaction was stirred at roomtemperature for 30 min. before adding aq. NaOH (6 M) (1.25 mL) and 30%H₂O₂ (1.25 mL). The reaction mixture became cloudy and was stirred atroom temperature for 1 h. The reaction mixture was extracted with EtOAc.The organic layers were washed with sat. aq. NaCl solution and driedover Na₂SO₄. The residue was purified by flash chromatography on silicagel (eluent: 40 to 100% EtOAc in hexanes) to give the title compound asa mixture of diastereomers.

Step C.(5R,6S)-1-((1S,3S)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-oneor(2S,3R)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlorophenyl)-2-(4-chlorophenyl)piperidine

To a solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(3-hydroxycyclopentyl)piperidin-2-one(Example 106, Step B) (175 mg, 0.433 mmol) in DMF (4 mL) at roomtemperature was added TBDMS-Cl (71.8 mg, 0.476 mmol) and imidazole (29.5mg, 0.433 mmol). The reaction mixture was stirred at room temperaturefor 18 h. Additional imidazole (29.5 mg, 0.433 mmol) and TBDMS-Cl (71.8mg, 0.476 mmol) were added. The reaction mixture was stirred at roomtemperature for 18 h and was then diluted with EtOAc, washed with aq. 1MLiCl solution, 1M HCl and sat. aq. Na₂CO.solution. The organic layer wasdried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by flash chromatography on silica gel (eluent: 0 to 100%EtOAc in hexanes) to give the title compound as the major single isomer.

Step D.(5R,6S)-1-((1S,3S)-3-(tert-Butyldimethylsilyloxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-oneor(2S,3R)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methylpiperidine

To(5R,6S)-1-((1S,3S)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-oneor(2S,3R)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlorophenyl)-2-(4-chlorophenyl)piperidinefrom above (Example 106, Step C) (104 mg, 0.201 mmol) was added toluene(15 mL) and the mixture was concentrated under reduced pressure. Thisstep was repeated three times. The residue was dissolved in inhibitorfree THF (2 mL) that was previously degassed with Ar and the mixture wascooled to 0° C. under Ar. Methyliodide (13.79 μL, 0.221 mmol) was addedfollowed by LHMDS (previously degassed with Ar) (1.0M in THF) (221 μL,0.221 mmol). The reaction mixture was warmed to room temperature andstirred under Ar for 24 h. Additional LHMDS (1.0 M in THF) (221 μL,0.221 mmol) was added and the reaction mixture was stirred at roomtemperature for 1 h. The reaction was quenched with sat. aq. NH₄Clsolution and extracted with EtOAc. The organic layers were dried overNa₂SO₄, filtered and the filtrate was concentrated in vacuo to providethe title compound.

Step E.(5R,6S)-3-Allyl-1-((1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-oneor(2S,3R)-5-Allyl-1-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methylpiperidine

To(5R,6S)-1-((1S,3S)-3-(tert-Butyldimethylsilyloxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-oneor(2S,3R)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methylpiperidinefrom above (Example 106, Step D) (107 mg, 0.201 mmol) was added toluene(15 mL) and the mixture was concentrated under reduced pressure. Thisstep was repeated three times. The residue was dissolved in inhibitorfree THF (2 mL) that was previously degassed with Ar and the mixture wascooled to 0° C. under Ar. Distilled allyl bromide (87 μL, 1.004 mmol)and LHMDS (1M in THF) (502 μL, 0.502 mmol) were added and the reactionmixture was warmed to room temperature and stirred at room temperaturefor 1 h before heating the reaction mixture at 50° C. under Arovernight. The reaction mixture was cooled to room temperature andadditional allyl bromide (87 μL, 1.004 mmol) and LHMDS (1.0 M in THF)(502 μL, 0.502 mmol) were added and the reaction mixture was heated to60° C. for 6 h under Ar. The reaction mixture was cooled to roomtemperature and the reaction was quenched with sat. NH₄Cl solution andextracted with EtOAc. The organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (eluent: 0 to 20% MTBE in hexanes) to givethe title compound as a mixture of diastereomers.

Step F.2-((5R,6S)-1-((1S,3S)-3-(tert-Butyldimethylsilyloxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((5R,6S)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-3-yl)aceticacid

The title compound was prepared from(5R,6S)-3-Allyl-1-((1S,3S)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-oneor(2S,3R)-5-Allyl-1-((1S,3R)-3-((tert-butyldimethylsilyl)oxy)cyclopentyl)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methylpiperidinefrom above (Example 106, Step E) as described in Example 95, Step D.

Step G.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3S)-3-hydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,3R)-3-hydroxycyclopentyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((5R,6S)-1-((1S,3S)-3-(tert-Butyldimethylsilyloxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((5R,6S)-1-((1S,3R)-3-((tert-Butyldimethylsilyl)oxy)cyclopentyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-3-yl)aceticacid from above (Example 106, Step F) (31 mg, 0.052 mmol) in THF (1.0mL) was added 1.0M TBAF in THF (262 μL, 0.262 mmol) at room temperature.The reaction mixture was stirred at room temperature for 19 h beforebeing concentrated under reduced pressure. The residue was purified byreversed phase preparatory HPLC (column: Gemini-NX C₁₈ 5 um column;Phenomonex, Torrance, Calif.; eluent: 45 to 75% MeCN+0.1% TFA inwater+0.1% TFA) to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.31 (3 H, s), 1.49-1.65 (3 H, m),1.65-1.90 (3 H, m), 2.06-2.19 (3 H, m), 2.68-2.78 (1 H, m), 3.05-3.18 (1H, m), 2.88 (1 H, d, J=15.1 Hz), 3.35-3.54 (1 H, m), 4.41-4.49 (1 H, m),4.68 (1 H, d, J=8.0 Hz), 6.85 (1 H, dt, J=7.4 and 1.7 Hz), 6.95-7.00 (2H, m), 7.09 (1 H, t, J=1.9 Hz), 7.15-7.26 (2 H, m), 7.30 (2 H, d, J=8.6Hz). Mass Spectrum (ESI) m/z=476 [M+H]⁺.

Example 1072-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)aceticacid

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)aceticacid

Step A.2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)pentanedial

To a solution of 454 mg (1.175 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(cyclopent-2-enyl)piperidin-2-one(Example 104, Step A) in THF (6 mL) was added water dropwise (3.5 mL)and tBuOH (0.2 mL). 4-methylmorpholine 4-oxide (207 mg, 1.763 mmol) wasadded followed by 4% aq. osmium(VIII) oxide (37.3 μL, 5.88 μmol). Thereaction mixture was stirred at room temperature for 18 h. Sodiumperiodate (704 mg, 3.29 mmol) was added and the cloudy reaction mixturewas stirred at room temperature for 90 min. Water (4 mL) was added andthe mixture was filtered and washed with EtOAc. The filtrate was dilutedwith EtOAc and the layers were separated. The combined organic layerswere washed with sat. Na₂S₂O₃, sat. aq. NaCl solution, dried over Na₂SO₄and concentrated in vacuo to provide the title compound.

Step B.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,5-dihydroxypentan-2-yl)piperidin-2-one

To a solution of2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)pentanedial(Example 107, Step A) (492 mg, 1.176 mmol) in MeOH (11 mL) was addedsodium borohydride (89 mg, 2.352 mmol) at room temperature. Evolution ofgas was observed. The reaction mixture was stirred at room temperaturefor 15 min and then concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (eluent: 50 to 100% EtOAcin hexanes and then 10% MeOH in DCM) to give the title compound.

Step C.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(tetrahydro-2H-pyran-3-yl)piperidin-2-one

To a solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1,5-dihydroxypentan-2-yl)piperidin-2-one(Example 107, Step B) (192 mg, 0.455 mmol) in THF (5 mL) at roomtemperature was added triphenylphosphine (119 mg, 0.455 mmol) followedby the dropwise addition of diisopropyl azodicarboxylate (89 μL, 0.455mmol). The reaction mixture turned light yellow during the addition andthen became colorless within 5 min. The reaction mixture was stirred atroom temperature for 1 h. The reaction mixture was diluted with EtOAcand washed with sat. aq. NaCl solution. The organic layer was dried overNa₂SO₄ and concentrated in vacuo. The residue was purified by flashchromatography on silica gel (eluent: 0 to 100% EtOAc in hexanes) togive the title compound as a mixture of diastereomers.

Step D.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)piperidin-2-one

The title compound was prepared from(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(tetrahydro-2H-pyran-3-yl)piperidin-2-one(Example 107, Step C) as described in Example 71, Step B.

Step E.(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)piperidin-2-one

The title compound was prepared as a mixture of stereoisomers from(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)piperidin-2-one(Example 107, Step D) as described in Example 71 Step C.

Step F.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)aceticacid Or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-tetrahydro-2H-pyran-3-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(tetrahydro-2H-pyran-3-yl)piperidin-2-one(Example 107, Step E) as described previously in Example 42, Step C. Theresidue was purified by reversed phase preparatory HPLC (column:Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to100% MeCN+0.1% TFA in water+0.1% TFA) to give the title compound as asingle, but unassigned stereoisomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.40 (3 H, s), 1.49-1.84 (3 H, m),2.01-2.16 (3 H, m), 2.39 (1 H, dd, J=12.3 and 4.3 Hz), 2.66-2.77 (1 H,m), 2.90-3.10 (2 H, m), 3.22-3.33 (1 H, m), 3.48 (1 H, br. s.),3.69-3.79 (1 H, m), 4.24 (1 H, t, J=10.5 Hz), 4.42 (1 H, d, J=9.4 Hz),6.72 (1 H, d, J=7.6 Hz), 6.89-7.04 (3H, m), 7.06-7.26 (4 H, m). MassSpectrum (ESI) m/z=476 [M+H]⁺.

Example 1082-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrazin-2-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyrazin-2-yl)piperidin-2-one

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) (100 mg, 0.27 mmol), 2-iodopyrazine (170 μL, 0.80mmol) and cesium carbonate (220 mg, 0.67 mmol) were dissolved in 2.7 mLof 1,4-dioxane. The reaction vessel was flushed with argon, copper (I)iodide (5.1 mg, 27 μmol) and TMEDA (11 μL, 80 μmol) were added, and thereaction mixture was allowed to stir at 110° C. for 15 hours. Thereaction mixture was cooled to room temperature, quenched with water andextracted (2×EtOAc). The combined organic layers were washed with sat.aq. NaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification of the residue byflash chromatography on silica gel (0 to 50% EtOAc/hexanes) provided thetitle compound as a colorless solid.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrazin-2-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyrazin-2-yl)piperidin-2-one(Example 108, Step A) as described in Example 42 Step C to provide awhite solid.

¹H NMR (400 MHz, MeOD) δ ppm 1.42 (s, 3 H), 2.30-2.39 (m, 1 H),2.39-2.49 (m, 1 H), 2.60 (d, J=14.67 Hz, 1 H), 3.07 (d, J=12.52 Hz, 1H), 3.71-3.81 (m, 1H), 5.50 (d, J=10.76 Hz, 1 H), 6.96-7.03 (m, 2 H),7.04-7.11 (m, 3 H), 7.12-7.17 (m, 2 H), 7.19 (br. s., 1 H), 8.16 (br.s., 1 H), 8.30 (s, 1 H), 8.62 (br. s., 1 H). MS (ESI) 470.2 [M+H]⁺.

Example 1092-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)piperidin-2-one

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) (90 mg, 0.24 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(125 mg, 0.60 mmol), diacetoxycopper (44 mg, 0.24 mmol) andN,N-dimethylpyridin-4-amine (88 mg, 0.72 mmol) were dissolved in 1.2 mLof toluene. Sodium bis(trimethylsilyl)amide (480 μL, 0.48 mmol) wasadded and the reaction apparatus was outfitted with a reflux condenserand was allowed to stir at 115° C. for 13 hours. The reaction mixturewas cooled to room temperature, quenched with water and extracted(2×EtOAc). The combined organic layers were washed with sat. aq. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. Purification of the residue by flashchromatography (0 to 60% EtOAc/hexanes) provided the title compound as acolorless solid.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(1-methyl-1H-pyrazol-4-yl)piperidin-2-one(Example 108, Step A) as described in Example 42, Step C to provide awhite solid.

¹H NMR (400 MHz, MeOD) δ ppm 1.42 (s, 3 H), 2.25-2.33 (m, 1 H),2.31-2.44 (m, 1 H), 2.60 (d, J=12.91 Hz, 1 H), 3.01 (d, J=13.30 Hz, 1H), 3.47-3.59 (m, 1 H), 3.68 (s, 3 H), 5.06 (d, J=10.37 Hz, 1 H),6.95-7.05 (m, 3 H), 7.09 (d, J=8.41 Hz, 2 H), 7.12-7.20 (m, 3 H), 7.24(s, 1 H), 7.49 (s, 1 H). MS (ESI) 472.2 [M+H]⁺.

Example 1102-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl)piperidin-3-yl)aceticacid

Step A. 1-(Pyrimidin-4-yloxy)-1H-benzo[d][1,2,3]triazole

To a solution of pyrimidin-4-ol (350 mg, 3.6 mmol) and(1H-benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphoniumhexafluorophosphate(V) (1.9 g, 4.4 mmol) in 24 mL of acetonitrile wasadded 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (820 μL, 5.5mmol) dropwise at room temperature. After the reaction mixture wasstirred for 1 hour, the reaction solvent was removed under reducedpressure. Purification of the residue by flash chromatography (0 to 70%EtOAc/hexanes) provided the title compound as a light yellow solid.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyrimidin-4-yl)piperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) (100 mg, 0.27 mmol) in 1.3 mL of DMSO was addedsodium hydride (60% suspension in mineral oil, 13 mg, 0.32 mmol) at roomtemperature. The reaction mixture was stirred for 5 minutes, and wastreated with 1-(pyrimidin-4-yloxy)-1H-benzo[d][1,2,3]triazole (Example110, Step A) (170 mg, 0.80 mmol). The reaction mixture was stirred at110° C. for 13 hours. The reaction mixture was cooled to roomtemperature, quenched with water and extracted (2×EtOAc). The combinedorganic layers were washed with sat. aq. NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. Purification of the residue by flash chromatography (0 to 45%EtOAc/hexanes) provided the title compound as a colorless solid.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl)piperidin-3-yl)acetaldehyde

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyrimidin-4-yl)piperidin-2-one(Example 110, Step B) (60 mg, 0.13 mmol) in a mixture of tetrahydrofuran(2.7 mL) and water (880 μL) was added osmium tetroxide (1.7 mg, 6.6μmol). After 5 minutes, sodium periodate (89 mg, 0.46 mmol) was addedand the reaction mixture was stirred for 14 hours. The reaction mixturewas filtered through Celite® (J.T. Baker, Phillipsberg, N.J.,diatomaceous earth) and washed with EtOAc and water. The organic layerwas washed with sat. aq. NaCl solution, dried over Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure. Purification ofthe residue by flash chromatography (0 to 75% EtOAc/hexanes, gradientelution) provided the title compound as a colorless solid.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl)piperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-4-yl)piperidin-3-yl)acetaldehyde(Example 110, Step C) (25 mg, 55 μmol) in a mixture of2-methylpropan-2-ol (1.0 mL) and 2-methyl-2-butene (55 μL, 2.0 M soln inTHF, 0.11 mmol) was added a solution of sodium chlorite (37 mg, 0.55mmol) and sodium dihydrogen phosphate (4.8 mg, 50 μmol) in 550 μL ofwater at room temperature. The reaction mixture was stirred for 1 hourbefore it was quenched with water and extracted (2×EtOAc). The combinedorganic layers were washed with sat. aq. NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. Purification of the residue by silica gel prep plate (10%MeOH/DCM) provided the title compound as a colorless solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 1.43 (s, 3 H), 2.21-2.27 (m, 1 H),2.29-2.36 (m, 1 H), 2.84-2.95 (m, 2 H), 3.34-3.42 (m, 1 H), 5.71 (d,J=9.78 Hz, 1 H), 6.85-6.92 (m, 3 H), 7.01 (d, J=8.31 Hz, 2 H), 7.10-7.16(m, 2 H), 7.18-7.22 (m, 1 H), 7.63 (d, J=5.38 Hz, 1 H), 8.49 (d, J=5.38Hz, 1 H), 8.82 (s, 1 H). MS (ESI) 470.2 [M+H]⁺.

Example 1112-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) (100 mg, 0.27 mmol) in 1.1 mL of DMSO was addedsodium hydride (60% suspension in mineral oil, 32 mg, 0.80 mmol) at roomtemperature. The reaction mixture was stirred for 15 minutes, and wastreated with 2,4-dichloropyrimidine (200 mg, 1.3 mmol). The reactionmixture was stirred at 60° C. for 5 hours. The reaction mixture wascooled to room temperature and quenched with water and extracted(2×EtOAc). The combined organic layers were washed with sat. aq. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. Purification of the residue by silica gel prepplate (50% EtOAc/hexanes) provided the title compound as a colorlesssolid.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-methylpiperidin-2-one(Example 111, Step A) as described in Example 110, Step C to provide awhite solid.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(2-chloropyrimidin-4-yl)-3-methyl-2-oxopiperidin-3-yl)acetaldehyde(Example 111, Step B) as described in Example 110 Step D to provide awhite foam.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.48 (s, 3 H), 2.29 (d, J=3.91 Hz, 1 H),2.33 (d, J=12.52 Hz, 1 H), 2.86 (d, J=14.87 Hz, 1 H), 3.06 (d, J=14.67Hz, 1 H), 3.31-3.41 (m, 1 H), 5.65 (d, J=10.37 Hz, 1 H), 6.83-6.87 (m, 1H), 6.88-6.93 (m, 2 H), 7.04-7.07 (m, 1 H), 7.07-7.10 (m, 2 H), 7.15 (m,1 H), 7.18-7.23 (m, 1 H), 7.70 (d, J=5.67 Hz, 1 H), 8.39 (d, J=5.7 Hz, 1H). MS (ESI) 504.0 [M+H]⁺.

Example 1122-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pyrimidin-2-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) and 2-chloropyrimidine as described in Example 111,followed by conversion to the acid as described in Example 71, Step F.

¹H NMR (500 MHz, CDCl₃) δ ppm 1.49 (s, 3 H), 2.34-2.40 (m, 2 H), 2.94(d, J=14.18 Hz, 1 H), 3.10 (d, J=13.45 Hz, 1 H), 3.50 (td, J=10.88 and3.91 Hz, 1 H), 5.46 (d, J=10.27 Hz, 1 H), 6.89 (d, J=7.34 Hz, 1 H),6.93-7.01 (m, 5 H), 7.11 (t, J=8.19 Hz, 1 H), 7.14-7.18 (m, 2 H), 8.56(d, J=4.9 Hz, 2 H). MS (ESI) 470.2 [M+H]⁺.

Example 1132-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-5-nitropyridin-2-yl)piperidin-2-one

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) and 2-chloro-3-methyl-5-nitropyridine as describedin Example 111, Step A to provide a light-yellow solid.

Step B.(3S,5R,6S)-3-allyl-1-(5-amino-3-methylpyridin-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methyl-5-nitropyridin-2-yl)piperidin-2-one(Example 113, Step A) (120 mg, 0.23 mmol) and tin(II) chloride dihydrate(260 mg, 1.1 mmol) were dissolved in 2.3 mL of ethyl acetate. Thereaction apparatus was outfitted with a reflux condenser and was stirredat 90° C. for 4 hours. The reaction mixture was cooled to roomtemperature, quenched with 1M NaOH and extracted (2×EtOAc). The combinedorganic layers were washed with sat. aq. NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. Purification of the residue by flash chromatography (0 to 90%EtOAc/Hex, gradient elution) provided the title compound as a colorlesssolid.

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl)piperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-1-(5-amino-3-methylpyridin-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 113, Step B) (89 mg, 0.185 mmol) in 1,4-dioxane (4.0 mL) andacetic acid (0.50 mL) was added 3.0M HCl (730 μL, 2.2 mmol) at 0° C.After the reaction was stirred for 5 minutes, hydrogen peroxide (6% wtaq., 95 μL, 0.185 mmol) was added dropwise, followed by sodium nitrite(46 mg, 0.74 mmol). The reaction mixture was stirred for 2 hours at 0°C. The reaction mixture was warmed to room temperature, quenched with 1MNaOH and extracted (2×EtOAc). The combined organic layers were washedwith sat. aq. NaCl solution, dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification of theresidue by flash chromatography (0 to 55% EtOAc/Hex, gradient elution)provided the title compound as a colorless solid.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetaldehyde

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl)piperidin-2-one(Example 113, Step C) as described in Example 110, Step C to provide awhite solid.

Step E.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(3-methylpyridin-2-yl)-2-oxopiperidin-3-yl)acetaldehyde(Example 113, Step D) as described in Example 110 Step D to provide awhite foam.

¹H NMR (500 MHz, CDCl₃) δ ppm 1.54 (s, 3 H), 2.12 (s, 3 H), 2.29 (dd,J=14.31 and 3.06 Hz, 1 H), 2.50 (t, J=13.82 Hz, 1 H), 2.92-3.01 (m, 1H),3.07-3.17 (m, 1 H), 3.56-3.67 (m, 1 H), 5.51 (d, J=11.00 Hz, 1 H),6.90-7.02 (m, 5 H), 7.05-7.15 (m, 4 H), 7.45 (d, J=7.09 Hz, 1 H), 8.30(d, J=3.67 Hz, 1 H). MS (ESI) 483.2 [M+H]⁺.

Example 1142-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl)piperidin-2-one

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) and 2-chloro-4-methyl-5-nitropyridine as describedin Example 113 Steps A-C to provide a white solid.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(4-methylpyridin-2-yl)piperidin-2-one(Example 114, Step A) (73 mg, 0.16 mmol) in 780 μL of tetrahydrofuranwas added water (1.0 mL), followed by 2-methylpropan-2-ol (100 μL) atroom temperature. The reaction mixture was treated with4-methylmorpholine 4-oxide (28 mg, 0.24 mmol), followed by osmiumtetroxide (2.0 mg, 7.8 μmol) and was stirred at room temperature for 2hours. The reaction mixture was treated with a 1.25 M solution of Jonesreagent (190 μL, 0.24 mmol) at room temperature and was stirred at roomtemperature for 1 hour. The reaction was quenched with water andextracted (3×EtOAc). The combined organic layers were washed with sat.aq. NaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification of the residue by HPLCon an Eclipse column (Agilent Technologies, Santa, Clara, Calif.) (20 to80% acetonitrile/water, gradient elution) provided the title compound asa colorless solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 1.49 (s, 3 H), 2.23 (s, 3 H), 2.28 (dd,J=14.2 and 3.2 Hz, 1 H), 2.42 (t, J=13.45 Hz, 1 H), 2.96 (m, 1 H), 3.04(m, 1 H), 3.39 (ddd, J=12.9, 10.2 and 3.1 Hz, 1 H), 5.57 (d, J=10.3 Hz,1 H), 6.81 (d, J=5.1 Hz, 1 H), 6.86-6.92 (m, 3 H), 6.99 (d, J=8.1 Hz, 2H), 7.08-7.13 (m, 2 H), 7.13-7.18 (m, 2H), 8.13 (d, J=5.1 Hz, 1 H). MS(ESI) 483.2 [M+H]⁺.

Example 1152-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. (Z)-2-((4-chlorobenzylideneamino)methyl)phenol

To a stirred suspension of 2-(aminomethyl)phenol, (4.0 g, 32.5 mmol) inethanol (65 mL) was added 4-chlorobenzaldehyde (3.86 mL, 32.8 mmol). Theresulting reaction mixture was stirred at rt for 3 h. The solvent wasremoved and 100 ml of toluene was added and concentrated in vacuumtwice. The resulting imine was dried under vacuum overnight and used inthe next step without further purification.

¹H NMR (500 MHz, DMSO-d6) δ ppm 9.47 (1 H, br. s.), 8.44 (1 H, s), 7.79(2 H, d, J=8.6 Hz), 7.51 (2 H, d, J=8.6 Hz), 7.16 (1 H, dd, J=7.3, 1.6Hz), 7.08 (1 H, td, J=7.6, 1.6 Hz), 6.72-6.87 (2 H, m), 4.71 (2 H, s).

Step B.2-(((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enylamino)methyl)phenol

To a solution of 1.42 g (5.3 mmol)(4S,5S)-2-allyl-2-chloro-3,4-dimethyl-5-phenyl-[1,3,2]-oxazasilolidine(prepared according to J. Am. Chem. Soc. 124, 7920, 2002) and1-chloro-3-vinylbenzene (1.69 g, 12.21 mmol) in DCM (12 mL) and DCE (12mL) was added 0.173 g (0.2 mmol) of1,3-bis-(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorophenylmethylene)(tricyclohexylphosphine)ruthenium(“Grubb's 2nd Generation Catalyst”). The resulting mixture was degassedtwo times and then heated to reflux for 8 h. The reaction mixture wascooled to room temperature. The imine, from above (Step A) (1.0 g, 4.07mmol) was added. The reaction mixture was heated to reflux for 14 h, andthen cooled to rt and quenched by adding 8 ml of ethanol. The reactionmixture was diluted with ethyl acetate (120 ml) and washed with water(30 ml) and sat. NaCl solution (30 ml). The combined organic layers weredried over MgSO₄, filtered and the filtrate was concentrated. Theresidue was purified by chromatography on silica gel, (eluent:hexane/ethyl acetate 90/10-65/35) to give the title compound.

¹H NMR (500 MHz, ACETONITRILE-d3) δ ppm 7.52 (2 H, d, J=8.3 Hz),7.23-7.37 (3 H, m), 7.10-7.17 (3 H, m), 7.06 (1 H, d, J=8.1 Hz),6.92-7.03 (2 H, m), 6.88 (1 H, td, J=7.5, 1.0 Hz), 6.14 (1 H, dt,J=16.4, 9.8 Hz), 5.72 (1 H, d, J=16.4 Hz), 5.47 (1 H, dd, J=9.8, 1.2Hz), 4.35-4.47 (1 H, m), 4.25-4.35 (1 H, m), 4.05 (1 H, d, J=13.4 Hz),3.78 (1 H, d, J=13.4 Hz). MS (ESI) [M+H]⁺, 398.0.

Step C.2-((N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamido)methyl)phenylacetate

To a solution of 1.1 g (2.76 mmol) of2-(((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enylamino)methyl)phenol(Example 115, Step B) and triethylamine (0.85 mL, 6.08 mmol) in amixture of THF (5.0 mL) and DCM (5.0 mL) was added acetic anhydride(0.55 mL, 5.80 mmol) at 0° C. The temperature of the reaction was slowlyallowed to rise to room temperature and the mixture was stirred atambient temperature overnight. When LCMS indicated completion of thereaction, 100 ml of ethyl acetate was added and the combined organicswere washed consecutively with water (30 ml), citric acid (30 ml, 1M),NaHCO₃ solution (30 ml) and sat. NaCl solution (30 ml), dried overMgSO₄, filtered and the filtrate was concentrated to give the titlecompound. The crude product was used without further purification.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.05-7.14 (4 H, m), 6.91-7.05 (6 H,m), 6.88 (1 H, d, J=7.4, Hz), 6.81 (1 H, t, J=7.5 Hz), 6.42 (1H, m),5.95 (1 H, dt, J=16.8, 9.6 Hz), 4.97-5.18 (2 H, m), 4.24-4.45 (2H, m),4.05 (1 H, q, J=7.0 Hz), 2.31 (3 H, s), 1.91 (3 H, s). MS (ESI) [M+H]⁺,482.0.

Step D.N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamide

A solution of 1.05 g (2.18 mmol) of2-((N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamido)methyl)phenylacetate (Example 115, Step C) and toluenesulfonic acid monohydrate (1.66g, 8.71 mmol) in toluene (15.0 mL) was heated to reflux for about 2 h.120 ml of ethyl acetate was added, and the combined organics were washedconsecutively with NaHCO₃ solution and sat. NaCl solution, dried overMgSO₄, filtered and the filtrate was concentrated. The crude mixture waspurified by preparative HPLC to give the title compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.08-7.15 (2 H, m), 7.02-7.08 (2 H,m), 6.92 (3 H, t, J=8.6, Hz), 6.81 (1 H, dd, J=3.5, 2.1 Hz), 5.83-6.07(2 H, m), 5.04-5.21 (3 H, m), 3.48 (1 H, t, J=9.3 Hz), 1.97 (3 H, s). MS(ESI) [M+H]⁺, 334.0.

Step E. (1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine

To a mixture of 4.1 g (12.27 mmol) ofN-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)acetamide(Example 115, Step D) and pyridine (1.20 mL, 14.72 mmol) in THF (35.0mL) was added 1.2 mL (13.5 mmol) of oxalyl chloride at 0° C. Theresulting light yellow slurry was stirred at 0° C. for 1.5 h.1,2-dihydroxypropane (1.80 mL, 24.53 mmol) was added in one portion andthe reaction was warmed to rt. The mixture was treated with ethanol(16.0 ml) followed by 6 N HCl (16.0 ml). The reaction mixture was heatedat 55° C. for 10 min and then cooled down to rt. When LCMS indicatedthat most SM was consumed, 200 ml of ethyl acetate was added, and theorganic layer was washed consecutively with NaHCO₃ solution and sat.NaCl solution, dried over MgSO₄, filtered and the filtrate wasconcentrated. The crude mixture was purified by flash chromatography onsilica gel to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21 (3 H, d, J=8.4 Hz), 7.03-7.17(3 H, m), 6.96 (1 H, s), 6.79 (1 H, ddd, J=6.2, 2.2, 2.0 Hz), 5.98 (1 H,dt, J=16.8, 9.8 Hz), 5.39 (1 H, d, J=16.8 Hz), 5.24 (1 H, d, J=10.2 Hz),4.14 (1 H, d, J=11.2 Hz), 3.76 (1 H, t, J=10.2 Hz). MS (ESI) [M+H]⁺,292.1.

Step F.(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-N-(dicyclopropylmethyl)but-3-en-1-amine

To a solution of 2.0 g (6.84 mmol) of(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example115, Step E), dicyclopropyl ketone (7.54 mL, 68.4 mmol), and acetic acid(1.96 mL, 34.2 mmol) in methanol (25.0 mL) was added sodiumcyanoborohydride (1.44 mL, 27.4 mmol) at rt. The resulting mixture wasstirred at 50° C. for 2 days. Acetic acid (1.5 ml) and sodiumcyanoborohydride (0.6 g) were added again and heating was continuedovernight. 200 ml of ethyl acetate was added, and the organic layer waswashed consecutively with K₂CO₃ solution and sat. NaCl solution, driedover K₂CO₃, filtered and the filtrate was concentrated under reducedpressure at 60° C. The mixture was purified by flash chromatography onsilica gel (eluent: DCM/MeOH, 95/5) to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.41 (4 H, m), 7.04-7.20 (2 H,m), 6.92-7.04 (1 H, m), 6.80 (1 H, dt, J=7.0, 1.6 Hz), 6.11 (1 H, ddd,J=16.8, 10.0, 9.8 Hz), 5.63 (1 H, d, J=16.8 Hz), 5.52 (1 H, d, J=10.0Hz), 4.47 (1 H, d, J=10.8 Hz), 4.06 (1H, t, J=10.0 Hz), 1.79 (1 H, t,J=9.4 Hz), 1.08-1.24 (1 H, m), 0.91-1.08 (2 H, m), 0.50-0.78 (3 H, m),0.29-0.50 (2 H, m), 0.24 (1 H, dq, J=9.9, 5.0 Hz), 0.09 (1 H, ddd,J=9.9, 5.2, 5.0 Hz). MS (ESI) [M+H]⁺, 386.0.

Step G.N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-N-(dicyclopropylmethyl)acrylamide

To a solution of 2.1 g (5.44 mmol) of(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-N-(dicyclopropylmethyl)but-3-en-1-amine(Example 115, Step F) and triethylamine (1.89 mL, 13.59 mmol) in THF(30.0 mL) was added acryloyl chloride (0.66 mL, 8.15 mmol) at 0° C. Theresulting reaction mixture was stirred at rt for 2 h. When LCMSindicated completion of the reaction, 100 ml of ethyl acetate was addedand the combined organics were washed consecutively with water (10 ml),citric acid (10 ml, 1M), NaHCO₃ solution (10 ml) and sat. NaCl solution(30 ml), dried over MgSO₄, filtered and the filtrate was concentrated.The crude product was purified by flash chromatography on silica gel(eluent: hexane/ethyl acetate, 90/10 to 20/80) to give the titlecompound.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.28 (3 H, br. s.), 6.94-7.17 (5 H,m), 6.87 (1 H, br. s.), 6.42 (1 H, m.), 6.20 (2 H, ddd, J=16.9, 9.8, 9.5Hz), 5.58 (1 H, d, J=10.3 Hz), 5.18 (1 H, d, J=16.9 Hz), 5.06 (2 H, dd,J=10.3, 1.3 Hz), 2.72 (1H, br. s.), 1.19-1.41 (1 H, m), 0.77-1.00 (2 H,m), 0.63 (3 H, d, J=5.6 Hz), 0.50 (1 H, br. s.), 0.43 (1 H, d, J=4.6Hz), 0.20 (1 H, br. s.), −0.28 (1 H, br. s.). MS (ESI) [M+H]⁺, 440.0.

Step H.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-5,6-dihydropyridin-2(1H)-one

To a solution of 2.1 g (4.77 mmol) ofN-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-N-(dicyclopropylmethyl)acrylamide(Example 115, Step G) in 50 mL of DCE was added 160 mg of1,3-bis-(2,4,6-trimethylphenyl)-2-(imidazolidinylidene)(dichlorophenylmethylene)(tricyclohexylphosphine)ruthenium(“Grubb's 2nd Generation Catalyst”). The resulting mixture was degassedtwo times and then heated to 70° C. for 18 h. Another 160 mg of Grubb's2nd Generation Catalyst was added at that time and heating was continuedfor another 18 h. The reaction mixture was cooled to room temperature.The solvent was removed and the residue was purified by chromatographyon silica gel (eluent: hexane/ethyl acetate, 90/10 to 20/80) to give thetitle compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.13-7.36 (8 H, m), 6.42 (1 H, d,J=9.8 Hz), 6.27 (1 H, ddd, J=9.8, 6.1, 1.3 Hz), 4.91 (1 H, s), 3.67 (1H, d, J=6.1 Hz), 3.28-3.44 (1 H, m), 0.42 (1 H, ddd, J=8.9, 4.6, 4.5Hz), 0.26-0.37 (3 H, m), 0.12-0.26 (3 H, m), −0.07-0.02 (1 H, m),−0.24-−0.12 (1 H, m), −0.34-−0.24 (1 H, m). MS (ESI) [M+H]⁺, 412.1.

Step I.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)piperidin-2-one

A solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-5,6-dihydropyridin-2(1H)-one(Example 115, Step H, 0.826 g, 2.003 mmol) and(1,5-cyclooctadiene)(pyridine) (tricyclohexylphosphine)iridium (i)hexafluorophosphate (0.129 g, 0.160 mmol) in DCM (60.0 ml) was saturatedwith hydrogen. The resulting mixture was stirred at rt under a hydrogenatmosphere for 2 h, then another 66.0 mg of(1,5-cyclooctadiene)(pyridine) (tricyclohexylphosphine)iridium (i)hexafluorophosphate were added. Stirring under hydrogen atmosphere wascontinued until LCMS indicated complete saturation of the double bond.The solvent was removed and the crude mixture was purified bychromatography on silica gel (eluting with ethyl acetate:hexane, 10:90)to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.11-7.32 (7 H, m), 6.98-7.11 (1 H,m), 4.96 (1 H, d, J=4.7 Hz), 3.26 (1 H, m.), 2.92-3.15 (1 H, m), 2.60 (2H, t, J=6.9 Hz), 2.09 (1 H, dddd, J=14.1, 7.3, 7.1, 4.9 Hz), 1.83-2.01(1 H, m), 0.80-0.94 (1 H, m), 0.45-0.61 (1 H, m), 0.12-0.41 (6 H, m),0.05 (1 H, dt, J=9.7, 4.8, Hz), −0.19-−0.04 (1 H, m). MS (ESI) [M+H]⁺,414.0.

Step J.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3(R,S)-methylpiperidin-2-one

The title compound was prepared form(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)piperidin-2-one(Example 115, Step I) as described in Example 68, Step C. The crudeproduct was purified by chromatography on silica gel (eluent: ethylacetate:hexane, 10:90) to give the title compound as colorless oil.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.16 (2 H, d, J=8.6 Hz), 7.00-7.14(6 H, m), 4.95 (1 H, d, J=2.2 Hz), 3.21 (1 H, br. s.), 2.85-2.99 (1 H,m), 2.40 (1 H, dt, J=10.3, 7.1 Hz), 1.68-1.87 (2 H, m), 1.21 (3 H, s),1.04-1.17 (1 H, m), 0.86 (1 H, d, J=4.2 Hz), 0.35-0.51 (1 H, m),0.12-0.28 (4 H, m), −0.04-0.12 (2 H, m), −0.34-−0.15 (1 H, m).

Step K.(3S/3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methylpiperidin-2-one

The title compound was obtained as a mixture of stereoisomers by using aprocedure similar to the one described in Example 68, Step D.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.06-7.23 (4 H, m), 6.91-7.06 (3 H,m), 6.69-6.86 (1 H, m), 5.79-5.98 (1 H, m), 5.03-5.26 (2 H, m), 4.81 (1H, d, J=9.6 Hz), 3.03-3.22 (1 H, m), 2.49-2.78 (2 H, m), 1.88-2.01 (2 H,m), 1.46 (1 H, s), 1.21 (2 H, s), 0.98-1.16 (1 H, m), 0.44-0.71 (3 H,m), 0.19-0.44 (3 H, m), −0.11-0.19 (3 H, m). MS (ESI) [M+H]⁺, 468.2.

Step L.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

A mixture of diastereomers of(3S/3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methylpiperidin-2-one(Example 115, Step K) was converted to a distereomeric mixture of theacids by a procedure similar to the one described in Example 71, Step F.Individual steroisomers were separated by reverse phase prep. HPLC(Sunfire™ Prep C₁₈ OBD 10 μm column (Waters, Milford, Mass.), gradientelution of 40% MeCN in water to 80% MeCN in water over a 30 min period,where both solvents contain 0.1% TFA) to give the title compound as thefaster eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.98 (1 H, dd, J=7.6, 6.5 Hz),7.00-7.29 (7 H, m), 6.86 (1 H, d, J=7.4 Hz), 4.93 (1 H, d, J=8.2 Hz),4.33 (1 H, d, J=5.1 Hz), 3.09-3.15 (1 H, m), 3.03 (1 H, d, J=15.1 Hz),2.69-2.80 (1 H, m), 2.08-2.17 (2 H, m), 1.35 (3 H, s), 1.14-1.21 (1 H,m), 0.53-0.73 (2 H, m), 0.41-0.51 (2 H, m), 0.27-0.40 (2 H, m),0.02-0.21 (3 H, m). MS (ESI) [M+H]⁺, 486.2.

Further elution and concentration in vacuo provided Example 116.

Example 1162-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(dicyclopropylmethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained from procedure 115 as the slower elutingisomer.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.10-7.33 (6 H, m), 6.95-7.03 (2 H,m), 6.73-6.83 (1 H, m), 4.80 (1 H, d, J=9.8 Hz), 3.18-3.23 (1 H, m),2.84 (1 H, t, J=13.4 Hz), 2.72-2.79 (1 H, m), 2.63-2.72 (1 H, m),2.32-2.39 (1 H, m), 1.77 (1 H, dd, J=13.2, 3.4 Hz), 1.64-1.68 (3 H, m),1.14 (1 H, m), 0.64-0.70 (1 H, m), 0.52-0.58 (1 H, m), 0.44-0.49 (2 H,m), 0.27-0.33 (2 H, m), 0.13-0.18 (2 H, m), −0.01 (1 H, m). MS (ESI)[M−H], 484.0.

Example 117((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)aceticacid

Step A.(E)-N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-2-phenylethenesulfonamide

To a solution of 5.33 g (18.24 mmol) of(1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-en-1-amine (Example115, Step E) in DCM (45.0 mL) was added N,N-diisopropylethylamine (4.8mL, 27.5 mmol), followed by trans-beta-styrenesulfonyl chloride (4.17 g,20.58 mmol). The resulting solution was stirred at ambient temperatureunder an N₂ atmosphere. After being stirred for 3.25 hours, the reactionwas diluted with water and extracted with DCM. The combined organiclayers were washed with sat. aq. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated. Purification by flashchromatography on silica gel (0 to 40% EtOAc in hexanes gradient)provided the title compound as a yellow solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ 7.30-7.41 (m, 3H), 7.12-7.17 (m, 2H),7.05-7.11 (m, 5H), 6.97-7.03 (m, 3H), 6.82-6.89 (m, 1H), 6.17 (d,J=15.41 Hz, 1H), 6.06-6.15 (m, 1H), 5.21-5.40 (m, 2H), 5.13 (d, J=5.62Hz, 1H), 4.60 (dd, J=5.87, 9.29 Hz, 1H), 3.54 (t, J=9.17 Hz, 1H). MS(ESI) 480.0 [M+Na]⁺.

Step B.(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,2-thiazin

To a degassed solution of 7.29 g (15.90 mmol) of(E)-N-((1S,2R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)but-3-enyl)-2-phenylethenesulfonamide(Example 117, Step A) in a 1:1 mixture of DCM (350 mL) and DCE (350 mL)was added Grubbs First Generation (1.20 g, 1.434 mmol). The resultingsolution was stirred at 70° C. for 20 hours. After cooling to roomtemperature, the reaction was concentrated under reduced pressure.Purification by flash chromatography on silica gel (0 to 2% MeOH in DCMgradient) provided the title compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ 7.20-7.29 (m, J=8.80 Hz, 3H), 7.11-7.19(m, 1H), 7.02 (d, J=8.31 Hz, 2H), 6.99 (t, J=/0.71 Hz, 1H), 6.86 (dd,J=2.69, 10.76 Hz, 1H), 6.79 (d, J=7.58 Hz, 1H), 6.44 (dd, J=2.20, 11.00Hz, 1H), 5.14 (d, J=11.00 Hz, 1H), 4.86 (t, J=10.76 Hz, 1H), 3.76 (td,J=2.35, 10.70 Hz, 1H). MS (ESI) 376.0 [M+Na]⁺.

Step C. (3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,2-thiazinan

A solution of 4.14 g (11.69 mmol) of(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-3,4-dihydro-2H-1,2-thiazin(Example 117, Step B) in dichloromethane (63.0 mL) was purged with argonthree times, and then Crabtree's catalyst (835.2 mg, 1.027 mmol) wasadded to the reaction mixture. The reaction was purged again with argon,and then a hydrogen atmosphere was placed over the reaction. Thesolution was stirred at ambient temperature for 15 hours, at which pointthe reaction was concentrated down to an oil. Purification by flashchromatography on silica gel (0 to 4% MeOH in DCM gradient) provided thetitle compound as a tan solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ 7.16-7.22 (m, 2H), 7.08-7.14 (m, 2H),6.99-7.07 (m, 3H), 6.82-6.88 (m, 1H), 4.67 (dd, J=5.01, 10.88 Hz, 1H),4.55 (d, J=4.65 Hz, 1H), 3.25-3.39 (m, 2H), 2.89-3.04 (m, 1H), 2.67(dddd, J=6.60, 10.39, 12.50, 14.52 Hz, 1H), 2.39 (qd, J=3.67, 14.43 Hz,1H). MS (ESI) 378.0 [M+Na]⁺.

Step D.(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-thiazinan

To a solution of 1.21 g (3.40 mmol) of(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,2-thiazinan (Example117, Step C) in DMF (8.5 mL) was added cesium carbonate (4.31 g, 13.23mmol), followed by 2-iodopropane (2.9 mL, 29.0 mmol). The resultingmixture was heated at 85° C. for 23 hours. After cooling to roomtemperature, the reaction mixture was diluted with water and extractedwith ethyl acetate. The combined organic layers were washed with sat.NaCl solution, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. Purification by flash chromatography on silica gel (0 to2% MeOH in DCM gradient) provided the title compound as a white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ 7.13-7.19 (m, 3H), 7.04-7.12 (m, 3H),7.00 (t, J=1.83 Hz, 1H), 6.75 (d, J=7.58 Hz, 1H), 4.51 (d, J=10.76 Hz,1H), 3.81 (td, J=6.94, 13.75 Hz, 1H), 3.40-3.49 (m, 1H), 3.25-3.39 (m,2H), 2.53 (ddt, J=6.85, 11.49, 13.45 Hz, 1H), 2.23 (tdd, J=2.96, 6.54,13.94 Hz, 1H), 1.36 (d, J=6.85 Hz, 3H), 1.07 (d, J=7.09 Hz, 3H). MS(ESI) 420.0 [M+Na]⁺.

Step E.(3S,4R,6R/6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan

To a degassed solution of 211.7 mg (0.531 mmol) of(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-thiazinan(Example 117, Step D) in THF (2.5 mL) was added allyl iodide (0.25 mL,2.74 mmol). The resulting solution was heated to 50° C. After 10minutes, a 1 M solution of lithium bis(trimethylsilyl)-amide in THF(0.86 mL, 0.860 mmol) was added dropwise, over one minute. After heatingat 50° C. for 20 hours, the reaction was cooled to room temperature,quenched with water (2 mL), and then concentrated under reducedpressure. Purification by flash chromatography on silica gel (0 to 100%DCM in hexanes gradient) provided the title compounds as a white solid.The ¹H NMR showed a 91:9 mixture of R/S allyl epimers.

A degassed solution of 98.6 mg (0.225 mmol) of the epimeric mixture inTHF (5 mL) was heated to 60° C. After 10 minutes, a 1 M solution oflithium bis(trimethylsilyl)-amide in THF (1.0 mL, 1.00 mmol) was added.The resulting solution was then stirred at 60° C. for 45 minutes, atwhich point methanol (275.0 μL, 6.80 mmol) was then added. The solutionwas heated for another 45 minutes at 60° C. Upon cooling to roomtemperature, the reaction was quenched with methanol (5 mL), thenconcentrated under reduced pressure. The material was purified byreverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column(Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in MeN/H₂O,gradient 30% to 95% over 25 minutes to provide the title compounds, as awhite solid. The ¹H NMR showed ˜2:1 mixture of epimers. Individualstereoisomers were separated by SFC (Chiralcel® AD-H column (Diacel,Fort Lee N.J.), 30 mm I.D.×250 mm, using 12 g/min of a 20 mM solution ofNH₃ in isopropyl alcohol and 68 g/min of CO₂ as the eluent) to give(3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan(t_(R)=1.62 min) as a white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.16-7.21 (m, 1 H), 7.06-7.15 (m, 5H), 7.00 (t, J=1.59 Hz, 1 H), 6.72 (d, J=7.58 Hz, 1 H), 5.71-5.88 (m, 1H), 5.11-5.24 (m, 2 H), 4.34 (d, J=11.00 Hz, 1 H), 3.99-4.11 (m, 1 H),3.46 (ddd, J=13.33, 10.76, 3.06 Hz, 1 H), 3.32-3.43 (m, 1 H), 2.85-2.96(m, 1 H), 2.43-2.61 (m, 2 H), 2.00 (dt, J=13.94, 2.45 Hz, 1 H), 1.35 (d,J=6.85 Hz, 3 H), 1.00 (d, J=7.09 Hz, 3 H). MS (ESI) 460.0 [M+Na]⁺.

Also obtained was(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan(t_(R)=1.87 min) as a white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.16 (d, J=8.31 Hz, 2 H), 7.10-7.14(m, 1 H), 7.04-7.10 (m, 3 H), 6.99 (t, J=1.59 Hz, 1 H), 6.74 (d, J=7.58Hz, 1 H), 5.76 (dddd, J=16.84, 10.24, 8.13, 6.11 Hz, 1 H), 5.10-5.22 (m,2 H), 4.57 (d, J=11.00 Hz, 1 H), 3.59 (dt, J=13.94, 6.97 Hz, 1 H),3.30-3.41 (m, J=11.49, 9.66, 4.71, 4.71 Hz, 1 H), 3.26 (ddd, J=12.65,10.82, 3.42 Hz, 1 H), 2.84-2.98 (m, 1 H), 2.21-2.33 (m, 2 H), 2.04-2.19(m, 1 H), 1.36 (d, J=6.85 Hz, 3 H), 1.13 (d, J=6.85 Hz, 3 H). MS (ESI)460.0 [M+Na]⁺.

Step F.((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)aceticacid

The title compound was obtained from(3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan(Example 117, Step E) by a procedure similar to the one described inExample 71, Step F. Purification by reversed phase preparative HPLCusing an Agilent Eclipse Plus C18 column (Agilent Technologies, Santa,Clara, Calif.), 0.1% TFA in MeCN/H₂O, gradient 30% to 95% over 25minutes, provided the title compound as a white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.12-7.19 (m, 3 H), 7.04-7.12 (m, 3H), 6.99 (br. s., 1 H), 6.73 (d, J=7.58 Hz, 1 H), 4.38 (d, J=11.00 Hz, 1H), 3.91-4.05 (m, 1 H), 3.84 (br. s., 1 H), 3.39-3.49 (m, 1 H), 3.24 (d,J=17.12 Hz, 1 H), 2.88 (dd, J=17.12, 10.27 Hz, 1 H), 2.66-2.79 (m, 1 H),2.02 (d, J=12.72 Hz, 1 H), 1.32-1.40 (m, 3 H), 1.03 (d, J=6.85 Hz, 3 H).MS (ESI) 478.0 [M+Na]⁺.

Example 118((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)aceticacid

The title compound was prepared from(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan(Example 117, Step E) as described in Example 117, Step F.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.07 (d, J=6.85 Hz, 2 H), 6.94-7.05(m, 4 H), 6.90 (br. s., 1 H), 6.65 (d, J=7.34 Hz, 1 H), 4.48 (d, J=11.00Hz, 1 H), 3.70-3.79 (m, 1 H), 3.48-3.57 (m, 1 H), 3.22-3.32 (m, 1 H),3.10 (dd, J=17.12, 4.65 Hz, 1 H), 2.46 (dd, J=17.12, 8.80 Hz, 1 H),2.22-2.34 (m, 1 H), 2.07 (d, J=12.47 Hz, 1 H), 1.25 (d, J=6.60 Hz, 3 H),1.01 (d, J=6.60 Hz, 3 H). MS (ESI) 478.0 [M+Na]⁺.

Example 119((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)aceticacid

Step A. Synthesis of(3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan

To a degassed solution of diisopropylamine (300 μL, 2.123 mmol) in THF(1.0 ml) was added dropwise at −78° C. n-butyllithium, 2.5 M in hexanes(800 μL, 2.000 mmol). After stirring the solution at −78° C. for 10 min,the reaction was warmed to room temperature. In a separate flask, adegassed solution of 111.9 mg (0.255 mmol) of(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan(Example 117, Step E) and methyl iodide (0.6 ml, 9.62 mmol) in THF (1.0ml) was heated to 50° C. After five minutes, the LDA solution was addeddropwise to the other flask, and stirring continued for 14 hours at 50°C. Upon cooling to room temperature, the reaction was quenched withwater (3 mL), then concentrated under reduced pressure. Purification byreverse-phase preparative HPLC using an Agilent Eclipse Plus C18 column(Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA in CH₃CN/H₂O,gradient 60% to 80% over 25 minutes provided the title compound as awhite solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.18 (br. s., 2 H), 7.03-7.14 (m, 4H), 6.96 (d, J=1.71 Hz, 1 H), 6.72 (d, J=7.34 Hz, 1 H), 5.64-5.93 (m, 1H), 5.18-5.28 (m, 2 H), 4.45 (d, J=10.76 Hz, 1 H), 3.61-3.75 (m, 1 H),3.30-3.44 (m, 1 H), 2.82-2.90 (m, 1 H), 2.74-2.82 (m, 1 H), 2.17-2.32(m, 1 H), 2.02 (dd, J=13.94, 3.18 Hz, 1 H), 1.42 (s, 3 H), 1.34 (d,J=6.85 Hz, 3 H), 1.11 (d, J=6.85 Hz, 3 H). MS (ESI) 474.1 [M+Na]⁺.

Step B.((3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)aceticacid

The title compound was prepared from(3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan(Example 119, Step A) as described in Example 1, Step F.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.08 (d, J=7.34 Hz, 2 H), 6.92-7.03(m, 4 H), 6.87 (br. s., 1 H), 6.63 (d, J=7.34 Hz, 1 H), 4.41 (d, J=11.00Hz, 1 H), 3.41-3.52 (m, 1 H), 3.29-3.36 (m, 1 H), 3.25 (d, J=14.92 Hz, 1H), 2.93 (d, J=15.16 Hz, 1 H), 2.21-2.36 (m, 2 H), 1.51 (s, 3 H), 1.23(d, J=6.60 Hz, 3 H), 1.05 (d, J=6.60 Hz, 3 H). MS (ESI) 492.1 [M+Na]⁺.

Example 120((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)aceticacid

Step A.(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)-1,2-thiazinan

To a degassed solution of 239.9 mg (0.602 mmol) of(3S,4R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-2-(2-propanyl)-1,2-thiazinan(Example 117, Step D) in THF (2.0 mL) was added iodomethane (60.0 μl,0.960 mmol), followed by dropwise addition of a 1 M solution of lithiumbis(trimethylsilyl)-amide in THF (640.0 μl, 0.640 mmol). After stirringat room temperature for 17 hours, the reaction was quenched with MeOH (3mL), then concentrated under reduced pressure. Purification by flashchromatography on silica gel (0 to 70% DCM in hexanes gradient) providedthe title compound as a white solid. The ¹H NMR showed 6% of the 6Sepimer was also isolated.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.14-7.18 (m, 2 H), 7.04-7.13 (m, 4H), 6.95-7.01 (m, 1H), 6.71-6.77 (m, 1 H), 4.57 (d, J=10.76 Hz, 1 H),3.54-3.63 (m, 1 H), 3.39-3.51 (m, 1 H), 3.23-3.39 (m, 1 H), 2.14-2.27(m, 2 H), 1.42 (d, J=6.85 Hz, 3 H), 1.34-1.38 (m, 3 H), 1.13 (d, J=6.85Hz, 3 H). MS (ESI) 434.0 [M+Na]⁺.

Step B.(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan

To a degassed solution of 174.7 mg (0.424 mmol) of(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)-1,2-thiazinan(Example 120, Step A) in THF (1.5 mL) was added allyl iodide (0.55 mL,6.02 mmol). The resulting solution was heated to 60° C. for 10 minutes,then a 1 M solution of lithium bis(trimethylsilyl)-amide in THF (2.0 mL,2.00 mmol) was added dropwise, over one minute. After heating at 60° C.for 17 hours, the reaction was cooled to room temperature, quenched withwater (2 mL), and then concentrated under reduced pressure. Purificationby reverse-phase preparative HPLC using an Agilent Eclipse Plus C18column (Agilent Technologies, Santa, Clara, Calif.), 0.1% TFA inMeCN/H₂O, gradient 40% to 95% over 25 minutes, provided the titlecompound as a white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.15-7.20 (m, 2 H), 7.03-7.13 (m, 4H), 6.97 (s, 1 H), 6.73 (d, J=7.34 Hz, 1 H), 5.72-5.89 (m, 1 H), 5.22(d, J=4.65 Hz, 1 H), 5.19 (s, 1 H), 4.47 (d, J=10.76 Hz, 1 H), 3.56-3.69(m, 1 H), 3.31-3.42 (m, 1 H), 2.69 (dd, J=13.82, 7.21 Hz, 1 H), 2.55(dd, J=13.82, 7.70 Hz, 1 H), 2.38 (t, J=13.45 Hz, 1 H), 1.87 (dd,J=13.94, 3.18 Hz, 1 H), 1.61 (s, 3 H), 1.33 (d, J=6.85 Hz, 3 H), 1.12(d, J=6.85 Hz, 3 H). MS (ESI) 474.1 [M+Na]⁺.

Step C.((3S,4R,6S)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-1,1-dioxido-2-(2-propanyl)-1,2-thiazinan-6-yl)aceticacid

The title compound was prepared from(3S,4R,6R)-4-(3-chlorophenyl)-3-(4-chlorophenyl)-6-methyl-2-(2-propanyl)-6-(2-propen-1-yl)-1,2-thiazinan(Example 120, Step B) as described in Example 1, Step F.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.15-7.23 (m, 2 H), 7.03-7.14 (m, 4H), 6.97 (br. s., 1 H), 6.73 (d, J=6.60 Hz, 1 H), 4.47 (d, J=10.52 Hz, 1H), 3.59-3.73 (m, 1 H), 3.42 (t, J=11.74 Hz, 1 H), 2.95-3.03 (m, 1 H),2.84-2.93 (m, 1 H), 2.47 (t, J=13.08 Hz, 1 H), 2.28 (d, J=13.94 Hz, 1H), 1.79 (br. s., 3 H), 1.30-1.39 (m, 3 H), 1.02-1.14 (m, 3 H). MS (ESI)492.1 [M+Na]⁺.

Example 1212-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A. Methyl 5-chloropicolinate

To a solution of 5-chloropyridin-2-carboxylic acid (309 g, 1.96 mol) inanhydrous MeOH (2 L) was slowly added thionyl chloride (299.7 mL, 4.12mol, 2.1 eq) at room temperature (cloudy solution became clear brownsolution during the addition of thionyl chloride). After the additionwas complete, the reaction mixture was heated to 50° C. and stirred atthis temperature overnight. The solvent and excess thionyl chloride wereremoved under reduced pressure and the crude product was azeotroped withtoluene twice. The resulting solid was transferred to a filter funneland washed with saturated aqueous NaHCO₃ until the filtrate was basic.The resulting solid was dissolved in dichloromethane (2 L) and washedwith saturated aqueous NaHCO₃. The organics were dried over sodiumsulfate, filtered and the filtrate was concentrated to provide the titlecompound as an off-white solid.

Step B. 2-(3-Chlorophenyl)-1-(5-chloropyridin-2-yl)ethanone

To a solution of 3-chlorophenylacetic acid (326.5 g, 1.91 mol, 0.95 eq)in THF (1.82 L) at −78° C. was slowly added NaHMDS (1M solution in THF,3.82 L, 3.82 mol, 2 eq) over 2 h 45 min while keeping the temperaturebelow −65° C. After the addition was complete, the reaction mixture wasstirred for 30 min at −78° C. A solution of methyl 5-chloropicolinate(326.5 g, 1.91 mol, Example 121, Step A) in THF (0.9 L) was added to theabove solution at −78° C. over 30 min. The reaction was stirred foranother 1 h and then allowed to warm to ambient temperature overnight.The reaction mixture was slowly transferred into a sat. aq. ammoniumchloride solution (4 L), extracted with ethyl acetate (2×8 L), and thenthe combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by flashchromatography on silica gel (eluent: DCM) provided the title compoundas a white solid.

Step C. methyl4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)-5-oxopentanoate

To a solution of 368.5 g (1.39 mol) of2-(3-chlorophenyl)-1-(5-chloropyridin-2yl)ethanone (Example 121, Step B)in dioxane (1.5 L) at 80° C. was added DBU (207 mL, 1.39 mole, 1 eq),followed by dropwise addition of methyl acrylate (124.7 mL, 1.39 mol, 1eq) at 80° C. The reaction was stirred at 80° C. for 1 h 30 min and thenallowed to cool to ambient temperature. It was quenched with 2 M aqueousHCl solution (56.5 eq) and then basified to pH 7 with saturated aqueousNaHCO₃. The aqueous layer was extracted with EtOAc (2×4 L). The combinedorganic layers were dried over Na₂SO₄, filtered and the filtrate wasevaporated. Purification by flash chromatography on silica gel (eluent:40 to 100% DCM/hexanes) provided the title compound as a yellow liquid.

Step D. (4R,5R)Methyl4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)-5-hydroxy pentanoate and(4S,5S)-methyl4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)-5-hydroxypentanoate

To a solution of 2-(3-chlorophenyl)-1-(5-chloropyridin-2-yl)ethanone(459.5 g, 1.3 mol, Example 121, Step C) in anhydrous MeOH (1.5 L) wasportionwise added sodium borohydride (14.8 g, 0.392 mol, 0.3 eq) at 0-5°C. The reaction was stirred at same temperature for 30 min then quenchedwith ice-water. The methanol was removed under reduced pressure. Theresidue was dissolved in ethyl acetate and washed with water. Theaqueous layer was extracted with ethyl acetate (3×2 L). The combinedorganic layers were washed with sat. NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure.Purification of the residue by flash chromatography on silica gel(eluent: 10 to 70% EtOAc/hexanes, gradient elution) provided the titlecompound as a yellow liquid.

Step E. (4R,5S)Methyl5-azido-4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)pentanoate and(4S,5R)-methyl5-azido-4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)pentanoate

To a solution of (4R,5R)-methyl4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)-5-hydroxypentanoate (432 g,1.22 mol, Example 121, Step D) and triethylamine (340 mL, 2.4 mol, 2 eq)in DCM (2.4 L) was added dropwise methanesulfonyl chloride (123.21 mL,1.59 mol, 1.3 eq) at 0-5° C. The reaction was stirred at 0-5° C. for 30min, then quenched slowly with ice water and extracted with DCM (2×2 L).The combined organic layers were washed with sat. aq. NaCl solution,dried over MgSO₄, filtered and the filtrate was concentrated underreduced pressure.

The crude mesylate thus obtained was dissolved in DMF (1.5 L) and to itwas added sodium azide (300 g, 4.6 mol, 3.8 eq). The reaction mixturewas heated to 90° C. (internal temperature) for 2 h. It was allowed tocool to ambient temperature. The reaction mixture was diluted with water(2 L) and extracted with ethyl acetate (2×4 L). The combined organiclayers were washed with sat. NaCl solution (2 L), dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Thecrude azide was carried directly to the next step without furtherpurification.

Step F.(5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one

Crude (4R,5S)-methyl5-azido-4-(3-chlorophenyl)-5-(5-chloropyridin-2-yl)pentanoate (463 g,1.22 mol, Example 121, Step E) was dissolved in 2.5 L THF/water (4:1).Trimethyl phosphine (1 M in THF, 1.46 L, 1.46 mol, 1.2 eq) was addedslowly at 0-5° C. The reaction was stirred for 30 min and then basifiedwith 2.0 M aqueous LiOH solution to pH 12. The reaction mixture wasstirred for another 30 min, and extracted to ethyl acetate (2×5 L). Thecombined organic layers were washed with sat. NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure.

Purification of the residue by flash chromatography on silica gel(eluent: 20-90% EtOAc/hexanes, gradient elution) followed byrecrystallization from EtOAc/hexanes provided trans5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one as a mixtureof stereoisomers. Individual stereoisomers were separated by chiral HPLC(flowrate: 100 ml/min on a Chiralcel® OD-H 10 cm I.D.×50 cm, 20 miccolumn (Daicel Chemical Industries LTD), using 25% isopropylalcohol/hexane as the eluent) to give the title compound (t_(R)=17-25min, earlier eluting peak) as a white solid.

¹H NMR (300 MHz, CDCl₃) δ 8.49 (d, J=2.34 Hz, 1H), 7.52 (dd, J=2.35 and8.21 Hz, 1H), 7.20-7.17 (m, 2H), 7.07 (s, 1H), 6.93-6.88 (m, 2H), 6.11(s, 1H), 4.70 (d, J=9.37 Hz, 1H), 3.20-3.13 (m, 1H), 2.61 (q, J=5.27 and8.2 Hz, 2H), 2.26-2.04 (m, 2H). Mass Spectrum (ESI) m/z=321 (M+1).

Step G. (S)-Ethyl2-((2S,3R)-3-(3-chlorophenyl)-2-(5-chloropyridin-2-yl)-6-oxopiperidin-1-yl)butanoate

To an ice-cooled solution of 9.93 g (30.9 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one(Example 121, Step F) in DMF (65 mL) was added 2.47 g (60 wt. % inmineral oil, 61.8 mmol) of sodium hydride. The resulting yellow slurrywas stirred at 0° C. for 5 min, then was warmed to room temperature andstirred for an additional 12 min. The reaction was re-cooled to 0° C.and 11.4 mL (77 mmol) of ethyl 2-bromobutyrate was added slowly viasyringe over 10 min. The resulting orange slurry was warmed to roomtemperature and stirred for 4.75 h, and then was quenched with saturatedaqueous ammonium chloride. The mixture was extracted with ethyl acetate(3×), and the combined organic layers were washed with water (2×) andsat. aq. NaCl solution (1×). The organic layer was dried over Na₂SO₄,filtered and the filtrate was concentrated. Purification of the residueby flash chromatography on silica gel (38 to 40% EtOAc/hexanes, gradientelution) provided the title compound as a light yellow solid.

Step H.(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

To an ice-cooled solution of 3.95 g (10.0 mmol) of (S)-ethyl2-((2S,3R)-3-(3-chlorophenyl)-2-(5-chloropyridin-2-yl)-6-oxopiperidin-1-yl)butanoate(Example 121, Step G) in ether (100 mL) was added 486 mg (90%, 20.1mmol) of lithium borohydride. The resulting light yellow slurry wasstirred at 0° C. for 3 h, and then was warmed to room temperature andstirred for an additional 3 h. The reaction was re-cooled to 0° C. andquenched by cautious addition of 1 N HCl until bubbling subsided. Themixture was extracted with EtOAc (3×), and the combined organic layerswere washed with saturated aqueous sodium chloride (1×). The organiclayer was dried over Na₂SO₄, filtered and the filtrate was concentrated.Purification of the residue by flash chromatography on silica gel (1 to7% MeOH/DCM, gradient elution) provided the title compound as a whitesolid.

Step I.(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one

To a solution of 2.03 g (5.2 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 121, Step H) and 877 mg (12.9 mmol) of imidazole in DMF (32 mL)was added 1.9 mL (7.3 mmol) of tert-butyldiphenylsilyl chloride. Theresulting light yellow solution was stirred at room temperature for 4.5h. The reaction was partitioned between water and EtOAc (2×), and thenthe combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by flashchromatography on silica gel (0 to 4% MeOH/DCM, gradient elution)provided the title compound as a white solid.

Step J.(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one

To a −78° C. solution of 3.19 g (5.05 mmol) of(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one(Example 121, Step I) and 347 μL (5.55 mmol) of methyl iodide in dry,degassed THF (40 mL) was added 6.82 mL (6.82 mmol) of a 1 M solution oflithium bis(trimethylsilyl)amide in THF slowly via syringe over 2 min.The yellow solution was warmed to 0° C. and stirred for 1.5 h, and thenwas warmed to room temperature and stirred for an additional 15 min. Thereaction was quenched with saturated aqueous ammonium chloride, andextracted with EtOAc (3×). The combined organic layers were dried overNa₂SO₄, filtered and the filtrate was concentrated. Purification of theresidue by flash chromatography on silica gel (0-15% MeOH/DCM, gradientelution) provided the title compound (mixture of C-3 epimers) as a whitesolid.

Step K.(5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one

To a solution of 2.95 g (4.57 mmol) of(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one(Example 121, Step J) and 7.91 mL (91.0 mmol) of allyl bromide in dry,degassed THF (22 mL) was added 68.6 mL (68.6 mmol) of a 1 M solution oflithium bis(trimethylsilyl)amide in THF slowly via syringe over 6 min atroom temperature. After 10 min, the orange solution was warmed to 50° C.and stirred for 24 h. At this time, 11.4 mL (11.4 mmol) of a 1 Msolution of lithium bis(trimethylsilyl)amide in THF and 790 μL (0.79mmol) of allyl bromide were added. The reaction was stirred for anadditional 6.25 h at 50° C., and then was cooled to room temperature andquenched with saturated aqueous ammonium chloride. The mixture wasextracted with EtOAc (3×), and the combined organic layers were driedover Na₂SO₄, filtered and the filtrate was concentrated. Purification ofthe residue by flash chromatography on silica gel (2 to 25%EtOAc/hexanes, gradient elution) provided the title compound (mixture ofC-3 epimers) as a light yellow solid.

Step L.(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

To an ice-cooled solution of 1.30 g (1.90 mmol) of(5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one(Example 121, Step K) in THF (55 mL) was added 11.37 mL (11.37 mmol) ofa 1 M solution of TBAF in THF. The orange solution was warmed to roomtemperature and stirred for 3.75 h. The reaction was partitioned between1 M HCl and EtOAc (2×), and then the combined organic layers were washedwith water (2×). The organic layer was dried over Na₂SO₄, filtered andthe filtrate was concentrated. Purification of the residue by flashchromatography on silica gel (0 to 10% MeOH/DCM, gradient elution)provided the title compound as a light yellow solid.

Step M.(S)-2-((5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanal

To a solution of 197 mg (0.44 mmol) of(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 121, Step L) in DCM (6 mL) was added 12 μL (0.66 mmol) of waterand 280 mg (0.66 mmol) of Dess-Martin periodinane. The resulting lightyellow slurry was warmed to room temperature and stirred for 50 min. Thereaction was quenched with saturated aqueous sodium thiosulfate, dilutedwith water, and extracted with DCM (2×). The combined organic layerswere washed with saturated aqueous sodium bicarbonate (1×) and saturatedaqueous sodium chloride (1×), and then were dried over Na₂SO₄, filteredand the filtrate was concentrated. Purification of the residue by flashchromatography on silica gel (0 to 7% MeOH/DCM, gradient elution)provided the title compound as a light yellow solid.

Step N.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one

The title compound was prepared from(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 121, Step M) as described in Example 91, Step A. Purificationof the crude product by flash chromatography on silica gel (3 to 10%MeOH/DCM, gradient elution) provided the title compound as a whitesolid.

Step O.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde

To a solution of 42 mg (0.08 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one(Example 121, Step N) in THF (6 mL) and water (2 mL) added a catalyticamount of osmium tetroxide. After 3 min, 87 mg (0.41 mmol) of sodiumperiodate was added. The resulting white slurry was stirred at roomtemperature for 4.25 h, and then filtered through a fritted funnel. Thefiltrate was partially concentrated under reduced pressure, and then wasdiluted with a mixture of water and saturated aqueous sodium chlorideand extracted with ethyl acetate (2×). The combined organic layers werewashed with saturated aqueous sodium thiosulfate and then saturatedaqueous sodium chloride. The organic layer was dried over Na₂SO₄,filtered and the filtrate was concentrated. Purification of the residueby reversed phase prep. HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column(Waters, Milford, Mass.), gradient elution of 35% MeCN in water to 75%MeCN in water over a 35 min period, where both solvents contain 0.1% TFAprovided the title compound as a white solid.

Step P.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of 16 mg (0.03 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)-2-oxopiperidin-3-yl)acetaldehyde(Example 121, Step O) and 1.0 mL (9.4 mmol) of 2-methyl-2-butene int-BuOH (3 mL) was added a solution of 28 mg (0.31 mmol) of sodiumchlorite and 4.6 mg (0.03 mmol) of sodium dihydrogenphosphate dihydratein water (1.6 mL). The resulting mixture was stirred at room temperaturefor 2 h, and then was quenched with 1 M HCl and extracted with EtOAc(3×). The combined organic layers were dried over Na₂SO₄, filtered andthe filtrate was concentrated. Purification of the residue by reversedphase prep. HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column (Waters, Milford,Mass.), gradient elution of 35% MeCN in water to 60% MeCN in water overa 35 min period, where both solvents contain 0.1% TFA provided the titlecompound as a white solid.

¹H NMR (400 MHz, CD₃OD) δ ppm 8.69 (1 H, d, J=2.4 Hz), 7.65 (1 H, dd,J=8.3 Hz, 2.5 Hz), 7.14-7.22 (2 H, m), 7.01-7.08 (2 H, m), 6.88-6.95 (1H, m), 4.85-4.90 (1 H, buried d), 3.94-4.09 (4 H, m), 3.42-3.53 (1 H,m), 3.07-3.24 (2 H, m), 2.88-3.01 (2 H, m), 2.73 (1 H, d, J=13.7 Hz),2.38 (1 H, t, J=13.9 Hz), 2.10 (1 H, dd, J=13.9 Hz. 3.5 Hz), 1.80-1.92(1 H, m), 1.41 (3 H, s), 1.39-1.47 (2 H, m), 1.13 (3 H, dd, J=6.5 Hz,4.9 Hz), 0.93-1.05 (3 H, br s). Mass Spectrum (ESI) m/z=534 (M+1).

Example 1222-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid

Step A.(5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(pentan-3-yl)piperidin-2-one

To a degassed solution of(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one (1.00g, 3.11 mmol, Example 121, Step F), 3-bromopentane (6.0 ml, 48.1 mmol)and tetrabutylammonium iodide (3.45 g, 9.34 mmol) in dry DMF (5.2 ml)was added 1.25 g (31 mmol) of a dispersion of 60% sodium hydride inmineral oil at 0° C. The reaction was heated to 90° for 8 h. Sat. aq.NaHCO₃/NaCl solution was added and the mixture was extracted with ethylacetate. The organic layers were washed with water and sat. NaClsolution, dried over Na₂SO₄, filtered and the filtrate was concentratedunder reduced pressure. Purification of the residue by flashchromatography on silica gel (eluent: 25 to 50% EtOAc/hexanes which hadbeen sparged with NH₃ gas, gradient elution) provided the titlecompound.

Step B.(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-(pentan-3-yl)piperidin-2-one

The title compound was prepared from(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(pentan-3-yl)piperidin-2-one(Example 122, Step A) by a procedure similar to the one described inExample 121, Steps J and K and was obtained as a mixture of epimers atC-3.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid

The title compound was obtained from(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-(pentan-3-yl)piperidin-2-one(149 mg, 0.335 mmol, mixture of stereoisomers at C-3, Example 122, StepB) by a procedure similar to the one described in Example 71, Step F.Purification by reversed phase preparatory HPLC (eluent: 50% MeCN/water(0.1% TFA), isocratic elution) using a Sunfire™ C18 OBD column, 10 uM,(30×150 mm), Waters Corp (Milford, Mass.) provided provided the titlecompound as the more polar, major isomer.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.53 (t, J=7.46 Hz, 3 H), 0.93 (t,J=7.46 Hz, 3 H), 1.20-1.34 (m, 1 H), 1.34-1.46 (m, 1 H), 1.49 (s, 3 H),1.62-1.78 (m, 1 H), 1.83 (ddd, J=14.61, 7.58, 7.40 Hz, 1 H), 1.99 (dd,J=13.69, 3.18 Hz, 1 H), 2.22 (t, J=13.57 Hz, 1 H), 2.72 (d, J=15.89 Hz,1 H), 2.88-2.99 (m, 1 H), 3.35 (d, J=15.89 Hz, 1 H), 3.43 (ddd, J=13.14,9.72, 3.06 Hz, 1 H), 4.50 (d, J=9.78 Hz, 1 H), 6.76 (dt, J=7.58, 1.22Hz, 1 H), 6.84 (d, J=8.07 Hz, 1 H), 6.98 (t, J=1.83 Hz, 1 H), 7.14 (t,J=7.70 Hz, 1 H), 7.53 (dd, J=8.07, 2.45 Hz, 1 H), 8.60 (d, J=2.20 Hz, 1H). Mass Spectrum (ESI) m/z=463 (M+1).

Example 1232-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid

The title compound was obtained in Example 122, Step C as the lesspolar, minor isomer.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.51 (t, J=7.46 Hz, 3 H), 0.94 (t,J=7.46 Hz, 3 H), 1.33-1.55 (m, 3 H), 1.73 (s, 3 H), 1.73-1.82 (m, 3 H),2.24 (t, J=13.69 Hz, 1 H), 2.49 (d, J=15.16 Hz, 1 H), 2.88 (d, J=14.92Hz, 1 H), 3.62 (ddd, J=13.88, 10.21, 3.55 Hz, 1 H), 4.42 (d, J=10.03 Hz,1 H), 6.70-6.82 (m, 2 H), 6.96 (t, J=1.83 Hz, 1 H), 7.09-7.24 (m, 2 H),7.52 (dd, J=8.07, 2.45 Hz, 1 H), 8.62 (d, J=2.45 Hz, 1 H). Mass Spectrum(ESI) m/z=463 (M+1).

Example 1242-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)piperidin-2-one

To a solution of 6.72 g (20.92 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one(Example 121, Step F) in DMF (˜0.5M) at 0° C. was slowly added adispersion of 60% sodium hydride in mineral oil (2.51 g, 62.8 mmol). Thereaction was stirred 0° C. for 30 min, followed by addition of1-(chloromethyl)-2,4-dimethoxybenzene (7.81 g, 41.8 mmol). Uponcompletion, the reaction was quenched at 0° C. with a small excess ofacetic acid (4.79 mL, 84 mmol). It was neutralized with sat. aq. NaHCO₃solution and extracted with ethyl acetate. The organic layer was driedover Na₂SO₄, filtered and the filtrate as concentrated under reducedpressure to yield a reddish oil. Purification by flash chromatography onsilica gel (eluent: 0 to 30% ethyl acetate/DCM, gradient elution)provided the title compound as a pale yellow oil.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.81-1.93 (m, 1 H), 2.00-2.11 (m, 1H), 2.38-2.50 (m, 1 H), 2.50-2.61 (m, 1 H), 3.30 (dt, J=6.60, 4.16 Hz, 1H), 3.63 (s, 3 H), 3.74 (d, J=14.43 Hz, 1 H), 3.80 (s, 3 H), 4.86 (d,J=4.40 Hz, 1 H), 5.23 (d, J=14.43 Hz, 1 H), 6.37 (d, J=2.20 Hz, 1 H),6.44 (dd, J=8.31, 2.45 Hz, 1 H), 6.84 (d, J=7.58 Hz, 1 H), 6.90-7.00 (m,2 H), 7.08 (t, J=7.83 Hz, 1 H), 7.11-7.16 (m, 1 H), 7.18 (d, J=8.31 Hz,1 H), 7.61 (dd, J=8.31, 2.45 Hz, 1 H), 8.56 (d, J=2.45 Hz, 1 H). MassSpectrum (ESI) m/z=471 (M+1).

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-oneand(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one

The title compound was prepared from(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)piperidin-2-one(Example 124, Step A) by a procedure similar to the ones described inExample 121, Steps J and K and was obtained as a mixture of epimers atC-3.

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one

(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one(3.6 g, 6.85 mmol, mixture of C-3 epimers, Example 124, Step B) wasdissolved in TFA (26.4 mL, 343 mmol) and the reaction was heated to 70°for 1.5 h. It was then cooled to ambient temperature and the TFA wasremoved by concentration under reduced pressure. The product wasazeotroped with heptanes, dissolved in DCM and the organic layer waswashed with sat. aq. NaHCO₃ solution and sat. NaCl solution.Purification by flash chromatography on silica gel (eluent: 35 to 45%EtOAc/hexanes which had been NH₃ sparged, gradient elution) provided thetitle compound as the more polar isomer as a white solid: (R_(f) in 75%EtOAc/Hexanes=0.44).

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.67-0.84 (m, 1 H), 1.10-1.25 (m, 3H), 1.60 (br. s., 1 H), 1.85-2.04 (m, 2 H), 2.32-2.50 (m, 1 H), 2.56 (d,J=8.31 Hz, 1 H), 3.19-3.33 (m, 1 H), 4.56-4.66 (m, 1 H), 4.99-5.14 (m, 2H), 5.68-5.84 (m, 1 H), 5.89 (br. s., 1 H), 6.72-6.84 (m, 2 H),6.92-7.01 (m, 1 H), 7.01-7.12 (m, 2 H), 7.12-7.23 (m, 1 H), 7.35-7.48(m, 1 H), 8.31-8.48 (m, 1 H). Mass Spectrum (ESI) m/z=375 (M+1).

Step D. (S) tert-Butyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanoate

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methylpiperidin-2-one(77 mg, 0.205 mmol, Example 124, Step C) in DMF (0.3 mL) was addedslowly 9.5 mg (0.24 mmol) of a dispersion of 60% sodium hydride inmineral oil followed by tert-butyl 2-bromobutanoate (92 mg, 0.410 mmol).The reaction was stirred at ambient temperature overnight, quenched withMeOH/HOAc, was diluted with EtOAc and water and extracted to EtOAc. Theorganics were dried over Na₂SO₄, filtered and the filtrate wasconcentrated. Purification by reversed phase preparatory HPLC (Sunfire™Prep C18 OBD 10 μm column (Waters, Milford, Mass.) (eluent: 70%acetonitrile, water, 0.1% TFA) provided the title compound, as well asits stereoisomer, (R)-tert-butyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanoate.

Step E. (S)-tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-3-(2-oxoethyl)piperidin-1-yl)butanoate

The example was prepared from (S)-tert-butyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanoate(Example 124, Step D) as described in Example 121, Step 0. Purificationof the residue by reversed phase preparatory HPLC(Sunfire™ Prep C18 OBD10 μm column (Waters, Milford, Mass.) (eluent: 55 to 75% acetonitrile,water, 0.1% TFA, gradient elution) provided the title compound as awhite solid after lyophilization.

Step F.2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from (S)-tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-2-oxo-3-(2-oxoethyl)piperidin-1-yl)butanoate (Example 124, Step E) as described inExample 121, Step P.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.46 (t, J=7.46 Hz, 2 H), 1.09-1.28(m, 2 H), 1.28-1.42 (m, 2 H), 1.42-1.46 (m, 2 H), 1.49 (s, 7 H),1.71-1.90 (m, 3 H), 1.93-2.04 (m, 1 H), 2.12-2.29 (m, 2 H), 2.89-2.97(m, 1 H), 2.99 (dd, J=7.70, 4.28 Hz, 1 H), 3.01-3.09 (m, 1 H), 3.61(ddd, J=13.02, 9.84, 3.55 Hz, 1 H), 4.73 (d, J=10.27 Hz, 1 H), 6.83 (d,J=7.58 Hz, 1 H), 6.94 (d, J=8.31 Hz, 1 H), 7.03 (s, 1 H), 7.11 (t,J=7.70 Hz, 1 H), 7.14-7.18 (m, 1 H), 7.56 (dd, J=8.31, 2.45 Hz, 1 H),8.61 (d, J=2.45 Hz, 1 H). Mass Spectrum (ESI) m/z=535 (M+1).

Example 1252-((3R,5S,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. 1-(4-Chlorophenyl)-2-(4-chloropyridin-2-yl)ethanone

To a solution of 4-chloro-2-methylpyridine (23.07 g, 181 mmol) andmethyl 4-chlorobenzoate (30.8 g, 181 mmol) in dry THF (500 mL) at 0° C.was added 1 M LiHMDS in THF (63.5 g, 380 mmol) slowly via a droppingfunnel. When complete, the reaction was quenched with NaHCO₃ solution,concentrated under reduced pressure, and extracted with ethyl acetate.The combined organics were dried over Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure to provide the title compound.

Step B. (4R,5R)-methyl5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)-5-hydroxypentanoate and(4S,5S)-methyl5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)-5-hydroxypentanoate

To a solution of 1-(4-chlorophenyl)-2-(4-chloropyridin-2-yl)ethanone(42.0 g, 158 mmol) and DBU (28.5 mL, 189 mmol, Example 125, Step A) indioxane (316 mL) at 80° C. was added methyl acrylate (15.73 mL, 174mmol), dropwise. The reaction was stirred at 80° C. for 30 min, at whichtime more methyl acrylate (2.86 mL, 31 mmol) was added. When thereaction was complete, it was cooled to 0° C. Methanol (500 mL) wasadded slowly, the reaction was cooled to 0° C. and NaBH₄ (5.97 g, 158mmol) was slowly added. The solution was concentrated under reducedpressure, and partitioned between ethyl acetate and 1 N NaOH. Theorganic layer was concentrated under reduced pressure. Purification byflash chromatography on silica gel (eluent: EtOAc/hexanes which had beenNH₃ sparged, gradient elution) provided the title compound.

Step C. (4S,5S)-methyl5-azido-5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)pentanoate and(4R,5R)-methyl 5-azido-5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)

The title compound mixture was prepared from methyl5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)-5-hydroxypentanoate (Example125, Step B) as described in Example 121, Step E, using 2.0 eq of NaN₃at 100° C. The residue was purified by flash chromatography on silicagel (eluent: 15 to 45% ethyl acetate/hexanes, gradient elution).

Step D.(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)piperidin-2-one

The title compound mixture was prepared from (4S,5S)-methyl5-azido-5-(4-chlorophenyl)-4-(4-chloropyridin-2-yl)pentanoate (racemiccompound mixture) (Example 125, Step C) as described in Example 121,Step F. The crude product was first purified by flash chromatography onsilica gel (eluent: 5 to 40% ethyl acetate/DCM, gradient elution), thenindividual stereoisomers were separated by chiral HPLC (250×30 mm AS-Hcolumn with 50 g/min IPA (0.2% DEA)+50 g/min CO₂ on Thar 350 SFC (TharTechnologies, Pittsburgh, Pa.)) to give the title compound as the fastereluting stereoisomer.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.60 (br. s., 3 H), 2.07 (dddd,J=13.60, 5.84, 2.93, 2.81 Hz, 2 H), 2.30-2.46 (m, 2 H), 2.54-2.72 (m, 4H), 2.96 (ddd, J=12.10, 9.54, 2.81 Hz, 2 H), 3.50 (s, 1 H), 4.98 (d,J=10.03 Hz, 2 H), 5.78 (br. s., 2 H), 6.81 (d, J=1.71 Hz, 2 H), 7.03 (d,J=8.31 Hz, 4 H), 7.09-7.17 (m, 2 H), 7.21 (d, J=8.07 Hz, 4 H), 8.46 (d,J=5.38 Hz, 2 H), Mass Spectrum (ESI) m/z=321 (M+1), (t_(R)=7.1 min on40% iPrOH/Hexanes on Chiracel OD analytical column)

Step E.(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)piperidin-2-oneor(5R,6R)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)piperidin-2-one

The title compound mixture was prepared from(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)piperidin-2-one or(5R,6R)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)piperidin-2-one(Example 125, Step D and 1-(chloromethyl)-2,4-dimethoxybenzene using asimilar procedure to that described in Example 124, Step A.

Step F.(3S,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-oneand(3R,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one

The title compound was prepared as a mixture of stereoisomers from(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one(Example 125, Step E) using a similar procedure to that described inExample 121, Steps J and K.

Step G.(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one

The title compound was prepared as a mixture of stereoisomers at the C3position from(5S,6S)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-1-(2,4-dimethoxybenzyl)-3-methylpiperidin-2-one(Example 125, Step F) in a similar procedure to that described inExample 124, Step C, followed by purification on silica gel, except thatthe reaction was warmed to ambient temperature rather than 70° and theeluents were 0 to 3% MeOH/DCM.

Step H. tert-butyl2-((3S,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanoateand tert-butyl2-((3R,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-1-yl)butanoate

To a solution of 100 mg, (0.266 mmol) of(5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methylpiperidin-2-one(Example 125, Step G; mixture of stereoisomers) in dry DMF (533 μL) atambient temperature was added a dispersion of 60% sodium hydride inmineral oil (15.99 mg, 0.400 mmol). The mixture was sonicated at 40° C.for 10 min, followed by addition of tert-butyl 2-bromobutanoate (119 mg,0.533 mmol). Stirred at ambient temperature for 24 h, then added 2 eqmore NaH, and stirred overnight. The reaction was quenched with a smallamount of 10% HOAc in MeOH, diluted with EtOAc and water and extractedto EtOAc×3. The combined organics were dried over Na₂SO₄, filtered andthe filtrate was concentrated under reduced pressure. Purification ofthe residue by preparatory RP-HPLC (Sunfire™ Prep C18 OBD 10 μm column(Waters, Milford, Mass., gradient elution of 55% MeCN in water to 75%MeCN in water over a 35 min period, where both solvents contain 0.1%TFA) yielded a mixture of 4 epimers including the title compound and theother 3 epimers. After HPLC, the product containing fractions wereconcentrated under reduced pressure, and extracted to ethyl acetate. Thecombined organics were dried over Na₂SO₄, filtered and the filtrate wasconcentrated.

Step I.2-((3R,5S,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-6-(4-chlorophenyl)-5-(4-chloropyridin-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(5R,6S)-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)piperidin-2-one(Example 125, Step H) as described in Example 121, Steps 0 and P.Purification of the residue by reversed phase HPLC (Sunfire™ Prep C18OBD 10 μm column (Waters, Milford, Mass.) (eluent: 55% MeCN/water (0.1%TFA) provided the title compound as a white solid.

1H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.56 (t, J=7.46 Hz, 3 H), 1.43 (s,3 H), 1.45-1.57 (m, 11 H), 2.17-2.35 (m, 3 H), 2.78-2.92 (m, 2 H), 3.09(dd, J=7.70, 3.79 Hz, 1 H), 3.57-3.66 (m, 1 H), 5.00 (d, J=10.51 Hz, 1H), 7.02 (d, J=1.71 Hz, 1 H), 7.11 (d, J=7.34 Hz, 2 H), 7.20 (dd,J=5.50, 1.83 Hz, 1 H), 7.24 (d, J=8.56 Hz, 2 H), 8.41 (d, J=5.38 Hz, 1H). Mass Spectrum (ESI) m/z=535 (M+1).

Example 1262-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A. (S)-Methyl2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate

To a solution of 1.3 g (3.61 mmol) of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 42, Step A) in DMF (14.43 mL) at 0° C. was added a dispersionof 60% sodium hydride in mineral oil (0.361 g, 9.02 mmol). The greyslurry was stirred at 0° C. for 30 minutes. Then methyl 2-bromobutanoate(1.246 mL, 10.83 mmol) was added. The mixture was warmed to roomtemperature and stirred at room temperature for 1 h. The mixture wasquenched with sat. NH₄Cl. The mixture was extracted with ethyl acetate.The organic layer was washed with water, 1 M LiCl (2×), and sat. aq.NaCl solution. The organic layer was dried over Na₂SO₄ filtered and thefiltrate was concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (80 g column; eluent: 10to 35% EtOAc in hexanes) to give the title compound as the less polar,major diastereomer.

Step B.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

To a solution of 710 mg (1.542 mmol) (S)-methyl2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanoate(Example 126, Step A) in Et₂O (15 mL) was added lithium borohydride(67.2 mg, 3.08 mmol) at 0° C. Evolution of gas was observed. Theresulting white slurry was stirred at 0° C. for 60 min. The mixture wasquenched with ice cold 1 M HCl. Evolution of gas was observed. Themixture was warmed to room temperature and extracted with EtOAc. Theorganic layer was washed with sat. aq. NaCl solution, dried over Na₂SO₄,filtered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by flash chromatography on silica gel (24 g column;eluent: 20 to 40% EtOAc in hexanes) to give the title compound.

Step C.(S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal

To a mixture of 2.00 g (4.63 mmol)(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 126, Step B) in water (0.125 g, 6.94 mmol) and DCM (50 mL) wasadded Dess-Martin periodinane (2.94 g, 6.94 mmol) at ambienttemperature. After being stirred for 1 h (no SM detected by TLC), thereaction was quenched by addition of 10 mL of 0.5 M Na₂S₂O₃, extractedwith DCM, and washed with sat. aq. NaHCO₃ solution and sat. aq. NaClsolution. The combined organic layers were dried over Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure. Purificationof the residue by chromatography on silica gel (80 g SiO₂, 5 to 20%EtOAc/hexanes) provided the title compound as a white foam.

Step D.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(methylamino)butan-2-yl)piperidin-2-one

To a solution of 1.67 g (3.88 mmol) of(S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butanal(Example 126, Step C) and acetic acid (6.60 mL, 116 mmol) in DCE (40 mL)was added 2 M methylamine in THF (19.40 mL, 38.8 mmol) and sodiumtriacetoxy hydroborate (3.29 g, 15.52 mmol) at room temperature. Thereaction was stirred for 2 days. The reaction was quenched with sat aq.NaHCO₃, extracted with EtOAc, and the combined organic layers werewashed with 1N NaOH and sat. aq. NaCl solution, dried over Na₂SO₄ andconcentrated under reduced pressure to provide the title compound as apale yellow oil, which was used without further purification in the nextstep.

Step E.N-(2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

To a solution of the free amine made in Example 126, step D (1.67 g,3.75 mmol) in DCE (15 mL) was added pyridine (6.06 mL, 75.0 mmol) andcyclopropanesulfonyl chloride (3.85 mL, 37.5 mmol) successively at 40°C. The reaction was stirred at 40° C. for 14 h. After that timeadditional 10 eq. pyridine and 10 eq. cyclopropanesulfonyl chloride wereadded. The reaction was stirred at 40° C. for 14 h. The reaction wasacidified with 10% citric acid and extracted with EtOAc. The combinedorganic layers were washed with saturated aq. NaHCO₃ solution and sat.aq. NaCl solution, dried over Na₂SO₄, and concentrated under reducedpressure. Purification by chromatography on silica gel (SiO₂, 25 g;eluent: 20% to 40% EtOAc/Hexanes) provided the title compound as a whitefoam.

Step F.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

N-(2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 126, Step D) was converted to the acid by a procedure similarto the one described in Example 1, Step H, to provide the crude titlecompound. The crude material was absorbed onto a plug of silica gel andpurified by chromatography, eluting with 60% to 80% EtOAc in hexane, toprovide a colorless oil. This was purified by reverse phase preparatoryHPLC (eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution)to provide the title compound as the second eluting peak fromreverse-phase-HPLC) as a white solid after lyophilization.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.51 (t, J=7.53 Hz, 3 H), 0.96-1.11(m, 2 H), 1.17-1.32 (m, 2 H), 1.61 (ddd, J=14.28, 7.83, 3.91 Hz, 1 H),1.88-2.02 (m, 2 H), 2.31-2.47 (m, 3 H), 2.68-2.77 (m, 1 H), 2.81 (br.s., 1 H), 2.86-3.10 (m, 2 H), 2.92 (s, 3 H), 3.23 (dd, J=15.45, 10.17Hz, 1 H), 4.67 (d, J=10.56 Hz, 1 H), 6.86 (m, 1 H), 6.94 (m, 3 H),7.11-7.20 (m, 2 H), 7.23-7.32 (m, 2 H); Mass Spectrum (ESI) m/z=567.2(M+1).

Example 1272-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoicacid

Step A.(3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one

To a solution of 615 mg (1.422 mmol)(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 126, Step B) in DMF (4741 μL) at 0° C. was added 1H-imidazole(97 mg, 1.422 mmol) followed by tert-butylchlorodiphenylsilane (473 μL,1.849 mmol). The mixture was stirred at 0° C. for 15 min and then warmedto room temperature. The mixture was stirred at room temperature for 30min and then quenched with sat. NH₄Cl. The mixture was extracted withEtOAc and the organic layer was washed with water, 1 M LiCl, and sat.aq. NaCl solution. The mixture was dried over Na₂SO₄ and concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel (24 g column; eluent: 0 to 30% EtOAc in hexanes) to givethe title compound.

Step B. 2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid

To a solution of(3R,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(816 mg, 1.216 mmol; Example 127, Step A) in water/acetonitrile/CCl₄ (7mL/5 mL/5 mL) at room temperature was added sodium periodate (1041 mg,4.87 mmol) and ruthenium chloride hydrate (27.4 mg, 0.122 mmol). Themixture was stirred vigorously at room temperature for 3 h. The mixturewas diluted with EtOAc and acidified with 1 M HCl. Sat. aq. NaClsolution was added and the mixture was filtered to remove the emulsion.The layers of the filtrate were separated. The organic layer was driedover Na₂SO₄ and concentrated under reduced pressure. The residue waspurified by flash chromatography on silica gel (24 g column; eluent: 0to 50% EtOAc in hexanes) to give the title compound.

Step C. Methyl2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetate

To a solution of2-((3S,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid (741 mg, 1.076 mmol; Example 127, Step B) in 10 mL of a 10%solution of MeOH in DCM at room temperature was added TMS-diazomethane(2.0M in ether) (807 μL, 1.614 mmol). Evolution of gas was observed andthe yellow mixture was stirred at room temperature for 45 min. MoreTMS-diazomethane (2.0M in ether) (807 μL, 1.614 mmol) was added and thereaction was stirred at room temperature for 45 min. The mixture wasconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (24 g column; eluent: 0 to 30% EtOAc inhexanes) to give the title compound.

Step D. Methyl2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)propanoate

Methyl2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)acetate(Example 127, Step C) was azetroped with toluene 3× and then dissolvedin THF (14 mL) under Ar and the mixture was cooled to −78° C. HMPA (236μL, 1.356 mmol) and LHMDS (1.0M in THF) (1356 μL, 1.356 mmol) were addedunder Ar at −78° C. The mixture was stirred at −78° C. for 30 min. Themixture color turned light yellow. Then iodomethane (110 μL, 1.763 mmol)was added and the reaction mixture was allowed to slowly warm to roomtemperature. The mixture was quenched with sat. NH₄Cl and the layerswere separated. The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified by flashchromatography on silica gel (2×50 g stacked VersaPak I-style,Spherical, Supelco, Bellenfonte, Pa.; eluent: 20 to 30% MtBE in hexanes)to give the title compound as the less polar, major diastereomer. Theretention time of the less polar diastereomer is 0.871 min (80-100%MeCN+0.1% TFA in water+0.1% TFA, over 1 minute). The retention time ofthe more polar diastereomer is 0.841 min (80 to 100% MeCN+0.1% TFA inwater+0.1% TFA, over 1 minute).

Step E. Methyl2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)propanoate

To a solution of methyl2-((3S,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)propanoate(285 mg, 0.398 mmol) (the less polar isomer from step D) in THF (1988μL) was added TBAF (1.0M in THF) (1590 μL, 1.590 mmol). The mixture wasstirred at room temperature for 16 h. The mixture was quenched with 1 MHCl and diluted with EtOAc. The organic layer was washed with sat. aq.NaCl solution, dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel(11 g VersaPak I-style, Spherical, Supelco, Bellenfonte, Pa.; eluent: 50to 75% MtBE in hexanes) to give the title compound.

Step F. Methyl2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate

A flask, containing a solution of methyl2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-2-oxopiperidin-3-yl)propanoate(195 mg, 0.408 mmol; Example 127, Step E) andN-methylcyclopropanesulfonamide (165 mg, 1.223 mmol) in toluene (2038μL) was evacuated and backfilled with Ar (5×). Thencyanomethylenetributylphosphorane (321 μL, 1.223 mmol) was added. Thelight brownish orange mixture was heated to 70° C. for 2 h. MoreN-methylcyclopropanesulfonamide (134 mg, 0.991 mmol) was added and themixture was heated to 70° C. for 2 h. The mixture was heated to refluxovernight and then cooled to room temperature. The mixture was dilutedwith EtOAc and sat. aq. NaCl solution. The layers were separated. Theorganic layer was dried over Na₂SO₄ and concentrated under reducedpressure. The residue was purified by flash chromatography on silica gel(4 g column eluent: 0 to 100% EtOAc in hexanes) to give the titlecompound.

Step G.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoicacid

To a solution of methyl2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate(56 mg, 0.094 mmol; Example 127, Step F) in MeOH/THF/H₂O (1 mL/1 mL/2mL) was added LiOH (3 M in water) (157 μL, 0.470 mmol) at roomtemperature. The slurry was heated to ˜100° C. for 3 h. The mixture wascooled to room temperature, acidified with 1 M HCl and extracted withEtOAc (2×). The organic layers were combined, dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Thecolorless film was purified by reverse phase preparatory HPLC (column:Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.; eluent: 0 to100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, J=6.65 Hz, 3 H), 0.95-1.07(m, 2 H), 1.20-1.26 (m, 5 H), 1.40 (dd, J=10.96, 7.24 Hz, 1 H),1.52-1.66 (m, 1 H), 1.85-1.93 (m, 1 H), 1.96-2.00 (m, 1 H), 2.22-2.36(m, 2 H), 2.70-2.79 (m, 1 H), 2.88-3.07 (m, 6 H), 3.13 (quin, J=7.19 Hz,1H), 4.67 (d, J=10.56 Hz, 1H), 6.89-6.92 (m, 1 H), 6.94-7.01 (m, 3 H),7.14-7.18 (m, 2 H), 7.25 (d, J=8.41 Hz, 2 H); Mass Spectrum (ESI)m/z=603 (M+23), 581 (M+1).

Example 128 (S)-tert-butyl2-((3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

Step A. (S)-tert-butyl2-((3R,5R,6S)-3-(2-amino-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

A solution of2-((3R,5R,6S)-1-((S)-1-tert-butoxy-1-oxobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (230 mg, 0.430 mmol; Example 67) in DMF (4.3 mL) was treated withN-(3-dimethyaminopropyl)-N′-ethylcarbodiimide hydrochloride (165 mg,0.86 mmol), 1-hydroxy-7-azabenzotriazole (117 mg, 0.86 mmol) and NaHCO₃(72.3 mg, 0.861 mmol) successively. After being stirred at rt for 0.5 h,7 M ammonia in methanol (6.2 mL, 4.30 mmol) was added dropwise and thereaction was stirred overnight. Then, the reaction was diluted (water),extracted (2×EtOAc), and washed (1×saturated NaHCO₃, and 2×sat. aq. NaClsolution). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by RP-HPLC (45 to 70%MeCN/H₂O (0.1% TFA), a gradient elution) provided the title compound asa white solid.

Step B. (S)-tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(cyanomethyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

A solution of (S)-tert-butyl2-((3R,5R,6S)-3-(2-amino-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(105 mg, 0.197 mmol; Example 128, Step A) and triethylamine (137 μL,0.984 mmol) in THF (3.3 mL) was treated with 2,2,2-trifluoroaceticanhydride (69.8 μL, 0.492 mmol) at 0° C. After being stirred at 0° C.for 3 h, the reaction was quenched (10% citric acid), extracted(2×EtOAc) and washed (sat. aq. NaCl solution). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure.Purification of the residue by chromatography on silica gel (12 g SiO₂,20 to 50% EtOAc/Hex, a gradient elution) provided the title compound asa colorless foam.

Step C. (S)-tert-butyl2-((3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

To a solution of (S)-tert-butyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(cyanomethyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(101 mg, 0.196 mmol; Example 128, Step B) in DMF (0.50 mL) was addedsodium azide (127 mg, 1.96 mmol) and NH₄Cl (105 mg, 1.96 mmol). Theresulting mixture was stirred at 90° C. for 5 days. Then, the reactionwas quenched (aq. 10% citric acid), extracted (2×EtOAc), and washed(3×sat. aq. NaCl solution). The combined organic layer was dried(Na₂SO₄) and concentrated under reduced pressure. Purification byRP-HPLC (60 to 85% AcCN/H₂O, gradient elution) provided the titlecompound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23-7.26 (2 H, m), 7.09-7.19 (2 H,m), 7.01 (1 H, t, J=1.9 Hz), 6.92 (2 H, d, J=8.6 Hz), 6.75-6.80 (1 H,m), 4.60 (1 H, d, J=10.8 Hz), 3.44-3.63 (2 H, m), 3.27 (1 H, br. s.),3.15 (1 H, dd, J=8.3, 3.4 Hz), 2.29-2.42 (2 H, m), 2.24 (1 H, d, J=3.3Hz), 1.49-1.52 (8 H, m), 1.34-1.40 (1 H, m), 1.32 (3 H, s), 0.55 (3 H,t, J=7.4 Hz); MS (ESI) 558.1 [M+H]⁺, 556.2 [M−H]⁻.

Example 1292-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((4-methoxybenzyl)amino)butan-2-yl)-3-methylpiperidin-2-one

To a solution of(S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(300 mg, 0.675 mmol; Example 91, Step C) and(4-methoxyphenyl)methanamine (131 μL, 1.01 mmol) in DCE (4.5 mL) wasadded sodium triacetoxyborohydride (429 mg, 2.03 mmol) at 0° C. inseveral portions. After being stirred at 25° C. for 18 h, the reactionwas quenched by adding ice-cold saturated aqueous NaHCO₃ and extracted(2×DCM). The combined organic layers were washed (1×sat. aq. NaClsolution) and concentrated under reduced pressure to provide the titlecompound as a yellow film. The product was used in the next step withoutfurther purification.

Step B.(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butan-1-ammonium2,2,2-trifluoroacetate

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-methoxybenzylamino)butan-2-yl)-3-methylpiperidin-2-one(370 mg, 0.654 mmol; Example 129, Step A) in acetonitrile (8.0 mL) andwater (1.6 mL) was added eerie ammonium nitrate (2.87 g, 5.23 mmol) at25° C. After being stirred at rt for 2 days, the reaction was quenched(sat. aq. NaCl solution), extracted (3×EtOAc), and washed (1×sat. aq.NaCl solution). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by RP-HPLC (35 to 70%MeCN/H₂O (0.1% TFA), a gradient elution) provided the title compound asa pale yellow powder.

Step C.N#S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)methanesulfonamide

(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butan-1-aminium2,2,2-trifluoroacetate (74 mg, 0.14 mmol; Example 129, Step B) wasdissolved in DCM at 0° C. and 2 N lithium hydroxide (0.34 mL, 0.68 mmol)was added and the resulting solution was stirred for 5 min at 0° C. Thesolution was extracted (2×DCM), washed (sat. aq. NaCl solution), dried(Na₂SO₄), and concentrated under reduced pressure to give the freeamine. To a solution of the free amine from above in DMF (0.34 mL) wasadded methanesulfonyl chloride (53 μL, 0.68 mmol) and pyridine (66 μL,0.820 mmol) successively at 0° C. After being stirred at 25° C. forovernight, the reaction was acidified (10% citric acid) and extracted(2×EtOAc) and washed (sat. aq. NaCl solution). The combined organiclayers were dried (Na₂SO₄), and concentrated under reduced pressure.Purification by RP-HPLC (45 to 80% MeCN/H₂O (0.1% TFA), a gradientelution) provided the title compound as a white powder.

Step D.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a rapidly stirring solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)methanesulfonamide(34 mg, 0.064 mmol; Example 91, Step C) in a mixture of water (0.55 mL),acetonitrile (0.37 mL), and CCl₄ (0.37 mL) was added sodium periodate(55 mg, 0.26 mmol) and ruthenium(III) chloride hydrate (1.5 mg, 6.5μmol). After being stirred vigorously for 20 h, the reaction wasacidified (10% citric acid) and diluted with EtOAc. The insolublematerial was removed by filtering through a pad of Celite® (J.T. Baker,Phillipsberg, N.J., diatomaceous earth). The filtrate was extracted(2×EtOAc) and washed (sat. aq. NaCl solution). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure.Purification by RP-HPLC (40 to 70% MeCN/H₂O (0.1% TFA), a gradientelution) provided the title compound as a white foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d, J=8.2 Hz), 7.10-7.18(2 H, m), 7.00-7.10 (2 H, m), 6.97 (1 H, s), 6.83 (1 H, d, J=7.2 Hz),4.99-5.20 (1 H, m), 4.87-4.97 (1 H, m), 4.74 (1 H, d, J=10.4 Hz),3.44-3.65 (1H, m), 3.10-3.33 (2 H, m), 3.02-3.09 (1 H, m), 2.99 (3 H,s), 2.96 (1H, s), 2.77 (1H, s), 2.36 (1 H, s), 1.94-2.05 (1 H, m),1.77-1.92 (1 H, m), 1.52-1.59 (1 H, m), 1.50 (3 H, s), 0.58 (3 H, t,J=7.3 Hz); MS (ESI) 541.0 [M+H]⁺, 539.0 [M−H]⁻.

Example 1302-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-5-oxohexan-3-yl)piperidin-3-yl)aceticacid

Step A.(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal

(Methoxymethyl)triphenylphosphonium chloride was dried at 80° C. undervacuum for 3 h. To a solution of the dried(methoxymethyl)triphenylphosphonium chloride (1.96 g, 5.71 mmol) in THF(10 mL) was added 0.5 M KHMDS in toluene (10.2 mL, 5.08 mmol) at −78° C.The color of the solution turned blood red in color. After stirring at0° C. for 30 min., a solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 91, Step C; 564 mg, 1.27 mmol) in THF (10.1 mL) was added at 0°C. dropwise. After being stirred at rt for overnight, the reaction wasquenched (sat NH₄Cl solution), extracted (2×EtOAc), and washed (sat. aq.NaCl solution). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by chromatography onsilica gel (SiO₂, 40 g, 15% and 20% EtOAc/Hexanes) provided the vinylether(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S,E)-1-methoxypent-1-en-3-yl)-3-methylpiperidin-2-one.To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S,E)-1-methoxypent-1-en-3-yl)-3-methylpiperidin-2-oneprepared above in acetonitrile (7.8 mL) was added 3 N hydrochloric acid(4.4 mL, 13 mmol) and the resulting solution was stirred at rt for 1.5h. Then, the reaction was extracted (2×EtOAc), and washed (sat. aq. NaClsolution). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure to provide the title compound as apale yellow film.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one

To a solution of(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal(540 mg, 1.18 mmol; Example 130, Step A) in THF (12 mL) was added 1.4 Mmethylmagnesium bromide in toluene and THF (75:25) (2.52 mL, 3.53 mmol)at 0° C. Then the reaction was allowed to warm to rt and stirred for 3h. The reaction was quenched (sat NH₄Cl solution), extracted (2×EtOAc),and washed (sat. aq. NaCl solution). The combined organic layers weredried (Na₂SO₄) and concentrated under reduced pressure to provide thecrude title compound as a mixture of diastereomers.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-5-oxohexan-3-yl)piperidin-3-yl)aceticacid

The title compound was obtained from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one(90 mg, 0.19 mmol; Example 130 Step B) as described in Example 71, StepF as a white foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23-7.27 (2 H, m), 7.06-7.17 (4 H,m), 7.00 (1 H, t, J=1.8 Hz), 6.81 (1 H, s), 4.92 (1 H, d, J=10.8 Hz),3.54-3.63 (1 H, m), 3.07 (3 H, d, J=15.7 Hz), 2.67 (1 H, d, J=15.8 Hz),2.50-2.60 (1 H, m), 2.19 (3 H, s), 2.12 (1 H, s), 1.97-2.07 (1 H, m),1.88-1.96 (1 H, m), 1.39 (3 H, s), 1.21-1.32 (1 H, m), 0.37 (3 H, t,J=7.5 Hz); MS (ESI) 490.0 [M+H]⁺, 488.0 [M−H]⁻.

Example 1312-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-5-oxohexan-3-yl)piperidin-2-one

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one(100 mg, 0.21 mmol; Example 130, Step B) by a procedure similar to theone described in Example 129, Step C.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-5-methylhexan-3-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-5-oxohexan-3-yl)piperidin-2-one(90 mg, 0.19 mmol; Example 131, Step A) in THF (1.9 mL) was added 1.4 Mmethylmagnesium bromide in toluene and THF (75:25) (408 μL, 0.571 mmol)at 0° C. Then the reaction was allowed to warm to rt and stirred for 4h. The reaction was quenched (sat NH₄Cl solution), extracted (2×EtOAc),and washed (sat. aq. NaCl solution). The combined organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure and purificationof the residue by chromatography on silica gel (12 g SiO₂, 30% and 35%EtOAc/Hex) provided the title compound as a colorless foam.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-hydroxy-5-methylhexan-3-yl)-3-methylpiperidin-2-one(73 mg, 0.15 mmol; Example 131, Step B) by a procedure similar to theone described in Example 71, Step F as a white foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d, J=7.8 Hz), 6.98-7.18(4 H, m), 6.95 (1 H, t, J=1.8 Hz), 6.70 (1 H, d, J=7.6 Hz), 4.90-5.38 (2H, m), 4.67-4.81 (1 H, m), 3.51 (1 H, s), 2.98-3.13 (2 H, m), 2.70 (1 H,d, J=15.1 Hz), 2.19 (1 H, t, J=13.8 Hz), 1.93 (2 H, d, J=13.3 Hz), 1.48(4 H, s), 1.16-1.28 (7 H, m), 0.53 (3 H, br. s.); MS (ESI) 506.0 [M+H]⁺,504.0 [M−H]⁻.

Example 1322-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)aceticacid (Isomer 1)

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,5S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,5R)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-5-oxohexan-3-yl)piperidin-2-one(120 mg, 0.254 mmol; Example 131, Step A) in THF (2.5 mL) was addedtrimethyl(trifluoromethyl)silane (113 μL, 0.762 mmol) at 0° C. and thereaction was stirred for 5 min. Then 1 M TBAF in THF (381 μL, 0.381mmol) was added slowly at 0° C. After being stirred at 0° C. for 20 min,the reaction was allowed to warm to rt. After being stirred at rt for 40min the reaction was quenched (sat aq. NH₄Cl), extracted (2×DCM), andwashed (2×sat. NaHCO₃ and 1×sat. aq. NaCl solution). The combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure. Purification of the residue by chromatography on silica gel(12 g SiO₂, 13% and 24% EtOAc/Hex) provided a less polar isomer and amore polar isomer.

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one(Less Polar Isomer)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J=8.2 Hz), 7.15-7.20(1 H, m), 7.07-7.14 (1 H, m), 6.88-7.06 (3 H, m), 6.69 (1 H, d, J=7.4Hz), 5.77-5.92 (1 H, m), 5.09-5.23 (2 H, m), 4.44-4.59 (1 H, m), 3.13 (1H, br. s.), 2.62 (2 H, d, J=7.4 Hz), 1.84-2.05 (3 H, m), 1.64-1.82 (2 H,m), 1.33 (3 H, s), 1.25-1.31 (5 H, m), 0.72-0.94 (3 H, m); MS (ESI)542.0 [M+H]⁺.

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one(More Polar Isomer)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.27 (2 H, m), 7.14-7.20 (1 H,m), 7.09-7.14 (1 H, m), 6.90-7.08 (3 H, m), 6.70 (1 H, d, J=7.4 Hz),5.86 (1 H, dd, J=17.4, 9.6 Hz), 5.12-5.22 (2 H, m), 4.44-4.56 (1 H, m),3.06-3.21 (1 H, m), 1.83-2.03 (2 H, m), 1.53-1.82 (3 H, m), 1.37-1.49 (1H, m), 1.29 (3 H, s), 1.23 (3 H, d, J=14.5 Hz), 0.62-0.94 (3 H, m); MS(ESI) 542.0 [M+H]⁺.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)aceticacid (Isomer 1)

The title compound was obtained from the less polar isomer of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-oneprepared in Step A by a procedure similar to the one described inExample 71, Step F as a white foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24-7.27 (2 H, m), 7.14-7.19 (1 H,m), 6.96-7.12 (3 H, m), 6.93 (1 H, t, J=1.7 Hz), 6.68 (1 H, d, J=7.6Hz), 4.58-4.67 (1 H, m), 2.98-3.14 (2 H, m), 2.71-2.81 (1 H, m), 2.17 (1H, s), 2.02 (2 H, s), 1.52-1.70 (1 H, m), 1.48 (3 H, s), 1.34 (5 H, s),0.19-0.93 (3 H, m); MS (ESI) 558.0 [M+H]⁺, 560.0 [M−H]⁻.

Example 1332-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-3-yl)aceticacid (Isomer 2)

The title compound was obtained from the more polar isomer of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxy-5-methylhexan-3-yl)piperidin-2-one(48 mg, 0.088 mmol; Example 132, Step A) by a procedure similar to theone described in Example 71, Step F as a white foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, br. s.), 6.96-7.19 (4 H,m), 6.93 (1 H, t, J=1.8 Hz), 6.69 (1 H, d, J=7.6 Hz), 4.60-4.70 (1 H,m), 3.01 (2 H, s), 2.75 (1 H, d, J=15.1 Hz), 2.11-2.21 (1 H, m), 2.02 (2H, s), 1.77-1.93 (1 H, m), 1.48 (6 H, s), 1.35 (3 H, br. s.), 0.39-0.71(3 H, m); MS (ESI) 560.0 [M+H]⁺, 558.0 [M−H]⁻.

Example 1342-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylmethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)piperidin-2-one

To a solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(70 mg, 0.16 mmol; Example 91, Step C) and acetic acid (271 μL, 4.73mmol) in ClCH₂CH₂Cl (2.6 mL) was added 2 M methylamine in THF (788 μL,1.58 mmol) and sodium triacetoxyborohydride (100 mg, 0.47 mmol) at rt.After being stirred at rt for 3 h, the reaction was quenched (sat aq.NaHCO₃), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). Thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure to provide the crude title compound as a pale yellowfilm. The product was used in the next step without furtherpurification.

Step B.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylmethanesulfonamide

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)piperidin-2-one(72 mg, 0.16 mmol; Example 134 Step A) in DMF (0.40 mL) was addedmethanesulfonyl chloride (61 μL, 0.79 mmol) and pyridine (76 μL, 0.95mmol) successively at 0° C. After being stirred at 25° C. for overnight,the reaction was acidified (10% citric acid) and extracted (2×EtOAc).The combined organic layers were washed (sat. aq. NaCl solution), dried(Na₂SO₄), and concentrated under reduced pressure. Separation by RP-HPLC(50 to 85% MeCN/H₂O (0.1% TFA) a gradient elution) provided the titlecompound as a pale yellow film.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylmethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylmethanesulfonamide(Example 134, Step B) described in Example AB, Step G.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21-7.27 (2 H, m), 7.10-7.17 (2 H,m), 6.92-7.07 (3 H, m), 6.87 (1 H, dd, J=6.5, 1.8 Hz), 4.78 (1 H, d,J=10.6 Hz), 4.12-4.27 (1 H, m), 2.97-3.15 (2 H, m), 2.84-2.90 (1 H, m),2.85 (3 H, s), 2.84 (3 H, s), 2.63-2.77 (2 H, m), 2.43 (1 H, t, J=13.9Hz), 1.88-1.97 (2 H, m), 1.55-1.68 (1 H, m), 1.51 (3 H, s), 0.50 (3 H,t, J=7.5 Hz); MS (ESI) 555.1 [M+H]⁺, 553.0 [M−H]⁻.

Example 1352-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1-cyclopropyl-1-hydroxypentan-3-yl)-3-methylpiperidin-2-one

To a solution of(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal(160 mg, 0.349 mmol; Example 130, Step A) in THF (3.5 mL) was added 0.5M cyclopropylmagnesium bromide in THF (2.09 mL, 1.05 mmol) at 0° C. Thenthe reaction was allowed to warm to rt and stirred for 3.5 h. Thereaction was quenched (sat NH₄Cl solution), extracted (2×EtOAc), andwashed (sat. aq. NaCl solution). The combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure to provide the titlecompound as a mixture of two diastereomers. The crude product was usedin the next step without further purification.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-1-oxopentan-3-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-1-hydroxypentan-3-yl)-3-methylpiperidin-2-oneprepared above in Step A (175 mg, 0.350 mmol) and water (9.5 μL, 0.52mmol) in DCM (3.9 mL) was added Dess-Martin periodinane (222 mg, 0.524mmol) at rt. After being stirred at rt for 40 min, the reaction wasquenched (1 M aq. Na₂S₂O₃), extracted (2×DCM), and washed (2×sat. NaHCO₃and 1×sat. aq. NaCl solution). The combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure. Purification of theresidue by chromatography on silica gel (12 g SiO₂, 15% and 25%EtOAc/Hex) provided the title compound as a colorless film.

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,5S)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,5R)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-1-oxopentan-3-yl)-3-methylpiperidin-2-oneprepared above in Step B (132 mg, 0.265 mmol) in THF (2.6 mL) was addedtrimethyl(trifluoromethyl)silane (117 μL, 0.794 mmol) at 0° C. and thereaction was stirred for 5 min. Then 1 M tetrabutylammonium fluoride inTHF (397 μL, 0.397 mmol) was added slowly at 0° C. Then the reaction wasallowed to warm to rt. After being stirred for 3 h, additionaltrimethyl(trifluoromethyl)silane (234 μL, 1.59 mmol) and 1 Mtetrabutylammonium fluoride in THF (794 μL, 0.794 mmol) were added at 0°C. and the reaction was allowed to warm to rt. After being stirred at rtfor 15 h, the reaction was quenched (sat. aq. NaCl solution), extracted(2×EtOAc), and washed (sat. aq. NaCl solution). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure.Purification of the residue by chromatography on silica gel (12 g SiO2,6% and 13% EtOAc/Hex) provided one of the title compounds as the lesspolar isomer and another one of the title compounds as the more polarisomer, successively.

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one(Less Polar Isomer)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J=8.2 Hz), 7.15-7.20(1 H, m), 7.07-7.14 (1 H, m), 6.88-7.06 (3 H, m), 6.69 (1H, d, J=7.4Hz), 5.77-5.92 (1 H, m), 5.09-5.23 (2 H, m), 4.44-4.59 (1 H, m), 3.13 (1H, br. s.), 2.62 (2 H, d, J=7.4 Hz), 1.84-2.05 (3 H, m), 1.64-1.82 (2 H,m), 1.33 (3 H, s), 1.25-1.31 (5 H, m), 0.72-0.94 (3 H, m); MS (ESI)568.2 [M+H]⁺.

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one(More Polar Isomer)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.27 (2 H, m), 7.14-7.20 (1 H,m), 7.09-7.14 (1 H, m), 6.90-7.08 (3 H, m), 6.70 (1 H, d, J=7.4 Hz),5.86 (1 H, dd, J=17.4, 9.6 Hz), 5.12-5.22 (2 H, m), 4.44-4.56 (1 H, m),3.06-3.21 (1 H, m), 1.83-2.03 (2 H, m), 1.53-1.82 (3 H, m), 1.37-1.49 (1H, m), 1.29 (3 H, s), 1.23 (3 H, d, J=14.5 Hz), 0.62-0.94 (3 H, m); MS(ESI) 568.2 [M+H]⁺.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-cyclopropyl-6,6,6-trifluoro-5-hydroxyhexan-3-yl)-3-methylpiperidin-2-one(Example 135, Step C, more polar product) by a procedure similar to theone described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.00-7.04 (2 H, m), 6.91-6.96 (1 H,m), 6.84-6.90 (1 H, m), 6.67-6.84 (3 H, m), 6.46 (1 H, d, J=7.6 Hz),4.29-4.45 (1 H, m), 2.76-2.91 (2 H, m), 2.51 (1 H, d, J=15.1 Hz),1.84-1.96 (1 H, m), 1.69-1.79 (1 H, m), 1.48-1.67 (1 H, m), 1.12-1.35 (6H, m), 0.62-0.81 (1 H, m), 0.01-0.51 (8 H, m); MS (ESI) 586.2 [M+H]⁺,584.0 [M−H]⁻.

Example 1362-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-6-methylheptan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(S)-4-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)hexanal

The title compound was prepared form(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal(106 mg, 0.231 mmol; Example 130, Step A) by a procedure similar to theone described in Example 130, Step A.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-6-hydroxyheptan-3-yl)-3-methylpiperidin-2-one

The title compound was prepared from(S)-4-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)hexanal(84 mg, 0.18 mmol; Example 136, Step A) by a procedure similar to theone described in Example 130, Step B as a colorless film. The crudeproduct was used in the next step without further purification

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-oxoheptan-3-yl)piperidin-2-one

The title compound was prepared from a mixture of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxyheptan-3-yl)-3-methylpiperidin-2-oneprepared above in Step B by a procedure similar to the one described inExample 129, Step C.

Step D.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-6-methylheptan-3-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-oxoheptan-3-yl)piperidin-2-oneprepared above in Step C (78 mg, 0.16 mmol) in THF (1.6 mL) was added1.4 M methylmagnesium bromide in toluene and THF (75:25) (344 μL, 0.481mmol) at 0° C. Then the reaction was allowed to warm to rt and stirredfor 2 h. The reaction was quenched (sat NH₄Cl solution), extracted(2×EtOAc), and washed (sat. aq. NaCl solution). The combined organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure.Purification of the residue by chromatography on silica gel (12 g SiO₂,33% and 43% EtOAc/Hex) provided the title compound as a colorless foam.

Step E.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-6-methylheptan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-6-hydroxy-6-methylheptan-3-yl)-3-methylpiperidin-2-one(Example 136, Step D) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d, J=8.4 Hz), 7.16 (1 H,dd, J=1.9, 1.1 Hz), 7.11 (1 H, d, J=7.6 Hz), 6.94 (3 H, t, J=1.8 Hz),6.70 (1 H, d, J=7.6 Hz), 5.01-5.25 (2H, m), 4.37 (1 H, d, J=10.4 Hz),3.06 (2 H, d, J=15.3 Hz), 2.93-3.03 (1 H, m), 2.71 (1 H, d, J=15.3 Hz),2.20 (1 H, s), 2.02 (1 H, s), 1.78-1.97 (2 H, m), 1.37-1.56 (7 H, m),1.22 (6 H, d, J=5.5 Hz), 0.55 (3 H, t, J=7.5 Hz); MS (ESI) 520.2 [M+H]⁺,518.0 [M−H]⁻.

Example 1372-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one

To a solution of(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal(100 mg, 0.218 mmol; Example 130, Step A) in THF (2.2 mL) was addedtrimethyl(trifluoromethyl)silane (97 μL, 0.66 mmol) at 0° C. and thereaction was stirred for 5 min. Then 1 M TBAF in THF (327 μL, 0.327mmol) was added slowly at 0° C. After being stirred at 0° C. for 40 min,the reaction was quenched (sat. aq. NaCl solution), extracted (2×EtOAc),and washed (sat. aq. NaCl solution). The combined organic layers weredried (Na₂SO₄) and concentrated under reduced pressure. Purification ofthe residue by chromatography on silica gel (12 g SiO₂, 13% and 23%EtOAc/Hex) provided the title compound as a mixture of twodiastereomers.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-oneprepared above in Step A (100 mg, 0.189 mmol) in DCM (2.1 mL) was addedwater (17 μL, 0.95 mmol) and Dess-Martin periodinane (161 mg, 0.378mmol) at rt and the resulting solution was stirred overnight. Thereaction was quenched (1 M aq. Na₂S₂O₃), extracted (2×DCM), and washed(2×sat. NaHCO₃ and 1×sat. aq. NaCl solution). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure toprovide the title compound as a colorless film. The product was used inthe next step without further purification.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6,6,6-trifluoro-5,5-dihydroxyhexan-3-yl)piperidin-2-one(Example 137, Step B) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.29 (2 H, br. s.), 7.06-7.20 (4 H,m), 6.97 (1 H, s), 6.76-6.82 (1 H, m), 4.74 (1 H, d, J=10.6 Hz),3.88-3.98 (1 H, m), 3.09-3.19 (2 H, m), 2.96 (1 H, s), 2.78 (2 H, s),2.08 (3 H, s), 1.38 (4 H, s), 0.42 (3 H, t, J=7.5 Hz); MS (ESI) 562.1[M+H]⁺, 560.0 [M−H]⁻.

Example 1382-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)aceticacid (Isomer 1)

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,6R)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,6S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-oxoheptan-3-yl)piperidin-2-one(169 mg, 0.347 mmol; Example 136, Step C) in THF (3.5 mL) was addedtrimethyl(trifluoromethyl)silane (154 μL, 1.04 mmol) at 0° C. and thereaction was stirred for 5 min. Then 1 M TBAF in THF (521 μL, 0.521mmol) was added slowly at 0° C. Then the reaction was allowed to warm tort. After being stirred at rt for 1.5 h, the reaction was quenched(water), extracted (2×EtOAc), and washed (water and sat. aq. NaClsolution). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. Purification of the residue bychromatography on silica gel (40 g SiO₂, 13%, 23% and 33% EtOAc/Hex)provided one of the title compounds as the less polar isomer and anotherone of the title compounds as the more polar isomer, successively

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one(Less Polar Isomer)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (2 H, d, J=8.2 Hz), 7.07-7.20(2 H, m), 6.91 (3 H, t, J=1.8 Hz), 6.65-6.74 (1 H, m), 5.82-5.97 (1 H,m), 5.13-5.24 (2 H, m), 4.33 (1 H, d, J=10.6 Hz), 3.78-3.99 (1 H, m),3.10-3.26 (1 H, m), 2.64 (2 H, dd, J=7.4, 4.5 Hz), 1.91-2.04 (2 H, m),1.68-1.78 (1 H, m), 1.62 (3 H, t, J=7.3 Hz), 1.33-1.46 (1 H, m), 1.29 (4H, s), 1.25 (3 H, s), 0.94-1.13 (1 H, m), 0.84 (3 H, t, J=7.3 Hz); MS(ESI) 556.2 [M+H]⁺.

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one(More Polar Isomer)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J=8.4 Hz), 7.08-7.20(2 H, m), 6.89-7.01 (3 H, m), 6.68-6.75 (1 H, m), 5.84 (1 H, s),5.13-5.23 (2 H, m), 4.28 (1 H, d, J=10.4 Hz), 3.09-3.22 (2 H, m), 2.62(2 H, d, J=7.2 Hz), 1.90-2.05 (2 H, m), 1.73-1.84 (2 H, m), 1.53-1.66 (3H, m), 1.35-1.48 (1 H, m), 1.31 (3 H, s), 1.24-1.29 (4 H, m), 0.66 (3 H,t, J=7.4 Hz); MS (ESI) 556.2 [M+H]⁺.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)aceticacid (Isomer 1)

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one(Example 138, Step A, less polar product) by a procedure similar to theone described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J=8.0 Hz), 7.14-7.19(1 H, m), 7.07-7.13 (1 H, m), 7.01 (2 H, br. s.), 6.92 (1 H, t, J=1.7Hz), 6.69 (1 H, d, J=7.6 Hz), 5.57-5.68 (1 H, m), 4.38 (1 H, d, J=10.4Hz), 3.52 (1 H, s), 3.17 (1 H, br. s.), 2.77-3.02 (2 H, m), 2.05-2.24 (2H, m), 1.75 (2 H, dd, J=11.8, 6.6 Hz), 1.53-1.65 (1 H, m), 1.48 (3 H,s), 1.34-1.45 (3 H, m), 1.29 (3 H, s), 0.71 (3 H, t, J=7.3 Hz); MS (ESI)574.2 [M+H]⁺, 572.0 [M−H]⁻.

Example 1392-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-3-yl)aceticacid (Isomer 2)

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-7,7,7-trifluoro-6-hydroxy-6-methylheptan-3-yl)piperidin-2-one(Example 138, Step A, more polar product) by a procedure similar to theone described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, s), 7.16-7.21 (1 H, m),7.09-7.15 (1 H, m), 7.01 (2 H, d, J=4.1 Hz), 6.93 (1 H, t, J=1.7 Hz),6.72 (1 H, d, J=7.6 Hz), 5.66-5.74 (1 H, m), 4.34 (1 H, d, J=10.2 Hz),3.09-3.27 (2 H, m), 2.98 (1 H, d, J=14.5 Hz), 2.74 (1 H, d, J=14.5 Hz),2.14-2.24 (1 H, m), 2.02-2.08 (1 H, m), 1.81 (2 H, dd, J=14.3, 7.2 Hz),1.52-1.70 (3 H, m), 1.50 (3 H, s), 1.29-1.38 (1 H, m), 1.27 (3 H, s),0.64 (3 H, t, J=7.3 Hz); MS (ESI) 574.2 [M+H]⁺, 572.0 [M−H]⁻.

Example 1402-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-7-methyloctan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(S)-5-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)heptanal

The title compound was prepared from(S)-4-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)hexanal(147 mg, 0.311 mmol; Example 136, Step A) by a procedure similar to theone described in Example 130, Step A.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-7-hydroxyoctan-3-yl)-3-methylpiperidin-2-one

To a solution of(S)-5-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)heptanalprepared above in Step A (138 mg, 0.284 mmol) in THF (2.8 mL) was added1.4 M methylmagnesium bromide in toluene and THF (75:25) (608 μL, 0.851mmol) at 0° C. Then the reaction was allowed to warm to rt and stirredfor 2 h. The reaction was quenched (sat NH₄Cl solution), extracted(2×EtOAc), and washed (sat. aq. NaCl solution). The combined organiclayer was dried (Na₂SO₄) and concentrated under reduced pressure toprovide the title compound as a colorless film.

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-7-oxooctan-3-yl)piperidin-2-one

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxyoctan-3-yl)-3-methylpiperidin-2-oneprepared above in Step B (143 mg, 0.285 mmol) by a procedure similar tothe one described in Example 131, Step A as a white solid.

Step D.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-7-methyloctan-3-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-7-oxooctan-3-yl)piperidin-2-oneprepared above in Step C (122 mg, 0.244 mmol) in THF (2.4 mL) was added1.4 M methylmagnesium bromide in toluene and THF (75:25) (522 μL, 0.731mmol) at 0° C. Then the reaction was allowed to warm to rt and stirredfor 2 h. The reaction was quenched (sat NH₄Cl solution), extracted(2×EtOAc), and washed (sat. aq. NaCl solution). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure andpurification of the residue by chromatography on silica gel (12 g SiO₂,30% and 40% EtOAc/Hex) provided the title compound as a colorless foam.

Step E.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-7-methyloctan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-7-hydroxy-7-methyloctan-3-yl)-3-methylpiperidin-2-one(Example 140, Step D) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J=8.0 Hz), 7.05-7.18(2 H, m), 6.92-7.05 (3 H, m), 6.70 (1 H, d, J=7.6 Hz), 4.42 (1 H, d,J=10.4 Hz), 3.05-3.18 (2 H, m), 3.00 (1 H, d, J=15.1 Hz), 2.72 (1 H, d,J=15.1 Hz), 2.11-2.26 (1 H, m), 1.97-2.08 (1 H, m), 1.79-1.92 (1 H, m),1.64-1.79 (1 H, m), 1.50-1.59 (2 H, m), 1.48 (3 H, s), 1.34-1.45 (3 H,m), 1.28-1.33 (1 H, m), 1.27 (3 H, s), 1.25 (3 H, s), 0.56 (3 H, t,J=7.4 Hz); MS (ESI) 534.1 [M+H]⁺, 532.2 [M−H]⁻.

Example 1412-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)piperidin-2-one(Example 134, Step A) by procedures similar to those described inExample 134, Steps B and C, substituting methanesuflonylchloride in StepB for the appropriate amount of cyclopropylsulfonyl chloride.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, br. s.), 7.10-7.17 (2 H,m), 6.80-7.09 (4 H, m), 4.79 (1 H, d, J=10.8 Hz), 4.13-4.30 (1 H, m),2.99-3.12 (2 H, m), 2.89 (4 H, s), 2.64-2.81 (2 H, m), 2.45 (1 H, t,J=13.8 Hz), 2.33 (1 H, s), 1.88 (2 H, dd, J=13.9, 2.7 Hz), 1.54-1.66 (1H, m), 1.50-1.54 (3 H, m), 1.22 (2 H, d, J=4.5 Hz), 1.02 (2 H, dd,J=8.0, 3.9 Hz), 0.51 (3 H, t, J=7.4 Hz); MS (ESI) 581.0 [M+H]⁺, 579.0[M−H]⁻.

Example 1422-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-cyclopropylmethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 91, Step C) by procedures similar to those described in Example134, Step A-C, substituting methylamine in Step A for the appropriateamount of cyclopropylamine.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.27 (2 H, m), 7.11-7.18 (2 H,m), 6.81-7.06 (4 H, m), 4.81 (1 H, d, J=10.6 Hz), 4.25-4.41 (1 H, m),3.08 (2 H, d, J=15.5 Hz), 2.95 (3 H, s), 2.81-2.90 (1 H, m), 2.73-2.80(1 H, m), 2.67 (1 H, d, J=15.5 Hz), 2.52 (2 H, s), 1.95-2.14 (1 H, m),1.77-1.88 (1 H, m), 1.53 (4 H, s), 0.70-0.92 (3 H, m), 0.59-0.69 (1 H,m), 0.50 (3 H, t, J=7.5 Hz); MS (ESI) 581.0 [M+H]⁺, 579.0 [M−H]⁻.

Example 1432-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)aceticacid (Isomer 1)

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,5S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,5R)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one

To a solution of(S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentanal(139 mg, 0.303 mmol; Example 130, Step A) in THF (3.0 mL) was addedtrimethyl(trifluoromethyl)silane (134 μL, 0.910 mmol) at 0° C. and thereaction was stirred for 5 min. Then 1 M TBAF in THF (455 μL, 0.455mmol) was added slowly at 0° C. Then, the reaction was allowed to warmto rt. After being stirred at rt for 1.5 h, the reaction was quenched(sat. aq. NaCl solution), extracted (2×EtOAc), and washed (sat. aq. NaClsolution). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. Purification of the residue bychromatography on silica gel (24 g SiO₂, 6% and 16% EtOAc/Hex) providedone of the title compounds as the less polar isomer and another one ofthe title compounds as the more polar isomer, successively.

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one(Less Polar Isomer)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.15-7.26 (3 H, m), 7.11 (1 H, t,J=7.7 Hz), 6.93 (3 H, t, J=1.9 Hz), 6.68 (1 H, dt, J=7.6, 1.5 Hz),5.83-5.95 (1 H, m), 5.17-5.26 (2 H, m), 4.38 (1 H, d, J=10.4 Hz),3.69-3.81 (1 H, m), 3.11-3.22 (1 H, m), 2.66 (2 H, d, J=7.6 Hz),1.92-2.12 (3 H, m), 1.72-1.89 (1 H, m), 1.49-1.60 (1 H, m), 1.25-1.37 (5H, m), 1.00 (1 H, none), 0.92-1.07 (3 H, m); MS (ESI) 528.1 [M+H]⁺.

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one(More Polar Isomer)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, dd, J=7.4, 1.4 Hz),7.15-7.20 (1 H, m), 7.11 (1 H, t, J=7.8 Hz), 6.90-7.05 (3 H, m), 6.70 (1H, dt, J=7.5, 1.5 Hz), 5.79-5.92 (1 H, m), 5.13-5.22 (2 H, m), 4.43 (1H, d, J=10.4 Hz), 3.90 (1 H, ddd, J=11.1, 6.6, 2.2 Hz), 3.09-3.22 (1 H,m), 2.53-2.71 (2 H, m), 1.90-2.05 (2 H, m), 1.56-1.86 (4 H, m),1.22-1.32 (4 H, m), 0.79 (3 H, t, J=7.4 Hz); MS (ESI) 528.1 [M+H]⁺.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S,5S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)aceticacid (Isomer 1)

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one(Step A, less polar product) by a procedure similar to the one describedin Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.06-7.27 (6 H, m), 6.94 (1 H, t,J=1.7 Hz), 6.68 (1 H, d, J=7.6 Hz), 4.58-5.15 (3 H, m), 4.42 (2 H, d,J=10.4 Hz), 3.88-4.01 (1 H, m), 3.19-3.28 (1 H, m), 2.86 (2 H, d, J=12.7Hz), 2.03-2.24 (2 H, m), 1.71-1.89 (1 H, m), 1.54-1.66 (1 H, m), 1.50 (3H, s), 1.26-1.40 (1 H, m), 0.97 (3 H, br. s.); MS (ESI) 546.0 [M+H]⁺,544.0 [M−H]⁻.

Example 1442-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-3-yl)aceticacid (Isomer 2)

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-6,6,6-trifluoro-5-hydroxyhexan-3-yl)piperidin-2-one(Example 143, Step A; more polar product) by a procedure similar to theone described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23-7.27 (2 H, m), 7.08-7.20 (2 H,m), 6.93-7.08 (3 H, m), 6.70 (1 H, dt, J=7.7, 1.4 Hz), 4.49 (1 H, d,J=10.4 Hz), 3.88-4.01 (1 H, m), 3.51 (1 H, s), 3.10-3.22 (1 H, m), 2.95(1 H, d, J=14.5 Hz), 2.75 (1 H, d, J=14.5 Hz), 2.20 (1 H, t, J=13.8 Hz),1.99-2.08 (1 H, m), 1.95 (1 H, d, J=2.3 Hz), 1.77 (1 H, dd, J=14.3, 7.2Hz), 1.52-1.70 (2 H, m), 1.48 (3 H, s), 0.72 (3 H, t, J=7.5 Hz); MS(ESI) 546.0 [M+H]⁺, 544.0 [M−H]⁻.

Example 1452-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Isomer 1)

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-5-oxohexan-3-yl)piperidin-3-yl)aceticacid (24 mg, 0.049 mmol; Example 130) in ether (0.40 mL) and MeOH (0.10mL) was added sodium borohydride (9.26 mg, 0.245 mmol) at 0° C. Then thereaction was allowed to warm to rt. After being stirred at rt for 1 h,the reaction was quenched (10% citric acid) and extracted (2×EtOAc). Thecombined organic layer was washed (sat. aq. NaCl solution), dried(Na₂SO₄), and concentrated under reduced pressure. Purification byRP-HPLC (30 to 70% MeCN/H₂O (0.1% TFA), a gradient elution) provided thetitle compound as the more polar isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.27 (2 H, m), 7.07-7.19 (2 H,m), 6.95-7.06 (3 H, m), 6.71 (1 H, dt, J=7.6, 1.6 Hz), 4.57 (1 H, d,J=10.2 Hz), 3.77-3.89 (1 H, m), 2.99-3.15 (2 H, m), 2.69 (1 H, d, J=14.9Hz), 2.23 (1 H, t, J=13.6 Hz), 1.81-1.99 (2 H, m), 1.52-1.64 (1 H, m),1.47 (3 H, s), 1.39 (1 H, d, J=2.0 Hz), 1.19 (3 H, d, J=6.3 Hz), 0.60 (3H, t, J=7.4 Hz); MS (ESI) 492.1 [M+H]⁺, 490.0 [M−H]⁻.

Example 1462-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-5-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Isomer 2)

Further elution from Example 145 provided the title compound as the lesspolar isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.04-7.27 (5 H, m), 6.91-7.04 (2 H,m), 6.70 (1 H, dt, J=7.7, 1.5 Hz), 4.47 (1 H, d, J=10.4 Hz), 3.75 (1 H,ddd, J=12.4, 6.1, 0.7 Hz), 3.15-3.27 (1 H, m), 2.96 (1 H, d, J=14.5 Hz),2.76 (1 H, d, J=14.7 Hz), 2.18 (1 H, t, J=13.8 Hz), 2.02-2.09 (1 H, m),1.59-1.71 (2 H, m), 1.50 (3 H, s), 1.26 (1 H, dd, J=16.8, 6.8 Hz),1.08-1.21 (2 H, m), 0.99-1.07 (3 H, m), 0.89 (3 H, br. s.); MS (ESI)492.1 [M+H]⁺, 490.0 [M−H]⁻.

Example 1472-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(N-(2,2,2-trifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)piperidin-2-one

To a solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(104 mg, 0.234 mmol; Example 130, Step A) in ClCH₂CH₂Cl (3.9 mL) wasadded 2,2,2-trifluoroethylamine (74 μL, 0.94 mmol) and sodiumtriacetoxyborohydride (248 mg, 1.17 mmol) at rt. After being stirred atrt overnight, the reaction was quenched (sat aq. NaHCO₃), extracted(2×EtOAc), and washed (sat. aq. NaCl solution). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure toprovide the title compound as a white solid. The product was used in thenext step without further purification.

Step B.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(2,2,2-trifluoroethylamino)butan-2-yl)piperidin-2-oneprepared above in Step A (60.9 mg, 0.115 mmol) in DCE (770 μL) was addedDMAP (70.5 mg, 0.577 mmol) and methanesulfonyl chloride (35.9 μL, 0.462mmol) successively at rt. After being stirred at rt for 3 h, pyridine(46.7 μL, 0.577 mmol), methanesulfonyl chloride (35.9 μL, 0.462 mmol),and DCE (0.77 mL) were added and the resulting solution was stirred for15 h.

The reaction was quenched (sat. NH₄Cl), and extracted (3×DCM). Thecombined organic layers were washed (water and sat. aq. NaCl solution),dried (Na₂SO₄), and concentrated under reduced pressure. Separation byRP-HPLC (10 to 90% MeCN/H₂O (0.1% TFA), a gradient elution) provided thetitle compound as a yellow solid.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(N-(2,2,2-trifluoroethyl)methylsulfonamido)butan-2-yl)piperidin-3-yl)aceticacid

The title compound was prepared fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-(2,2,2-trifluoroethyl)methanesulfonamide(Step B) by a procedure similar to the one described in Example 71, StepF.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21-7.28 (2 H, m), 7.11-7.20 (2 H,m), 6.74-7.10 (4 H, m), 4.65 (1 H, d, J=10.8 Hz), 4.32-4.50 (1 H, m),4.11 (1 H, d, J=7.8 Hz), 3.48-3.65 (1 H, m), 2.94-3.19 (6 H, m),2.79-2.92 (1 H, m), 2.75 (1 H, d, J=14.7 Hz), 2.42 (1 H, t, J=13.9 Hz),1.85-2.12 (2 H, m), 1.50 (4 H, s), 0.48 (3 H, t, J=7.4 Hz); MS (ESI)623.0 [M+H]⁺, 621.0 [M−H]⁻.

Example 1482-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-3-chloropropane-1-sulfonamide

(3S,5R,6S)-3-Allyl-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one2,2,2-trifluoroacetate (76 mg, 0.14 mmol; Example 129, Step B) wasdissolved in DCM, basified (1 N LiOH), extracted (3×DCM), and washed(sat. aq. NaCl solution). The combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure to provide the freeamine. To a solution of the free amine in DCE (0.68 mL) was addedpyridine (55 μL, 0.68 mmol) and 3-chloropropane-1-sulfonyl chloride (96mg, 0.54 mmol) successively at rt. The reaction was stirred at rt for 5h. Then additional pyridine (55 μL, 0.68 mmol) and3-chloropropane-1-sulfonyl chloride (96 mg, 0.54 mmol) was added. Afterbeing stirred overnight, the reaction was quenched (10% citric acid),extracted (3×EtOAc), and washed (saturated aq. NaHCO₃ and sat. aq. NaClsolution). The combined organic layers were dried (Na₂SO₄), andconcentrated under reduced pressure. Separation by RP-HPLC (10 to 90%MeCN/H₂O (0.1% TFA), gradient elution) provided the title compound as ayellow solid.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methylpiperidin-2-one

To a solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-3-chloropropane-1-sulfonamideprepared above in Step A (36.1 mg, 0.062 mmol) in DMF (1.2 mL) was addedDBU (46.4 μL, 0.308 mmol) at rt. After being stirred at rt overnight,the reaction was quenched (10% citric acid), extracted (3×EtOAc), andwashed (saturated aq. NaHCO₃ and sat. aq. NaCl solution). The combinedorganic layers were dried (Na₂SO₄) and concentrated under reducedpressure to provide the title compound as a pale brown film.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-methylpiperidin-2-one(Step B)) by a procedure similar to the one described in Example 71,Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27 (2 H, d, J=8.0 Hz), 7.10-7.19(2 H, m), 6.97 7.10 (3 H, m), 6.83 (1 H, d, J=7.4 Hz), 4.87 (1 H, d,J=0.6 Hz), 3.33 (2 H, t, J=6.6 Hz), 3.24 (2 H, t, J=7.5 Hz), 3.09 (2 H,d, J=15.3 Hz), 2.96 (2 H, d, J=2.3 Hz), 2.74 (1 H, d, J=15.3 Hz),2.37-2.51 (3 H, m), 1.90-2.02 (2 H, m), 1.53 (4 H, s), 0.49 (3 H, t,J=7.5 Hz); MS (ESI) 567.1 [M+H]⁺, 565.0 [M−H]⁻.

Example 1492-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one

To a solution of oxalyl dichloride (78 μL, 0.87 mmol) in DCM (1.5 mL) at−60° C. was added a solution of DMSO (93 μL, 1.30 mmol) in DCM (1.5 mL)under N₂. After being stirred for 2 min, a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-oneprepared in example 151, Step C (200 mg, 0.434 mmol) in DCM (1.5 mL) wasadded and the resulting solution was stirred for 15 min. at −60° C.Then, triethylamine (305 μL, 2.17 mmol) was added to the reactionsolution. After being stirred at rt for 20 min, the reaction wasquenched (water), extracted (2×EtOAc), and washed (2×sat. aq. NaClsolution). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. Purification by combi flash (SiO₂,24 g, 20% and 30% EtOAc/Hexanes) provided the title compound as acolorless foam.

Step B.((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxy-2-methylpent-1-en-3-yl)-3-methylpiperidin-2-one

(Methoxymethyl)triphenylphosphonium chloride was dried at 80° C. undervacuum for 2 h. To a solution of the dried(methoxymethyl)triphenylphosphonium chloride (673 mg, 1.96 mmol) in THF(3.5 mL) was added 0.5 M KHMDS in toluene (3.49 mL, 1.75 mmol) at −78°C. The solution resulted in a blood red color. After addition, thereaction was stirred at 0° C. for 30 min and a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-oneprepared above in Step B (200 mg, 0.436 mmol) in THF (3.5 mL) was addeddropwisely at 0° C. The reaction was allowed to warm to rt and stirredfor 1.5 h. Then the reaction was quenched (sat NH₄Cl solution),extracted (2×EtOAc), and washed (brine). The combined organic layerswere dried (Na₂SO₄) and concentrated under reduced pressure.Purification by combi flash (SiO₂, 24 g, 15% and 20% EtOAc/Hexanes)provided the title compound as a colorless film.

Step C.(2S,3S)-3-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-methylpentanaland(2R,3S)-3-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-methylpentanal

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxy-2-methylpent-1-en-3-yl)-3-methylpiperidin-2-oneprepared above in Step B (179 mg, 0.368 mmol) in acetonitrile (3.7 mL)was added 3 N hydrochloric acid (1.5 mL, 4.5 mmol) at rt. After beingstirred at rt for 1.5 h, the reaction was extracted (2×EtOAc), andwashed (2×brine). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure provided the title compounds as amixture of stereoisomers (dr=7:3) as a pale yellow film.

Step D.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,4R)-4-methyl-5-oxohexan-3-yl)piperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S,4S)-4-methyl-5-oxohexan-3-yl)piperidin-2-one

To a solution of(2S,3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-methylpentanaland(2R,3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-methylpentanalprepared above in Step C (177 mg, 0.375 mmol) in THF (3.076 ml) wasadded 1.4 M methylmagnesium bromide in toluene and THF (75:25) (0.803ml, 1.12 mmol) at 0° C. Then the reaction was allowed to warm to rt andstirred for 2 h. The reaction was quenched (sat NH₄Cl solution),extracted (2×EtOAc), and washed (brine). The combined organic layer wasdried (Na₂SO₄) and concentrated under the reduced pressure to provide acrude seconday alcohol product.

To a solution of the crude seconday alcohol product (183 mg, 0.375 mmol)in DCM (4.2 mL) was added water (14 μL, 0.75 mmol) anddess-martinperiodinane (196 mg, 0.462 mmol) successiviely. After beingstirred ar rt for overnight, the reaction was quenched (1 M aq.Na₂S₂O₃), extracted (2×DCM), and washed (2×sat. NaHCO₃ and 1×brine). Thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. Purification of the residue by chromatography onsilica gel (24 g SiO₂, 13%, 27% and 37% EtOAc/Hex) provided a less polarand more polar isomer, successively.

Less polar isomer: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d,J=8.0 Hz), 7.03-7.17 (4 H, m), 6.94-6.99 (1 H, m), 6.81-6.87 (1 H, m),5.12-5.23 (2 H, m), 4.58 (1 H, d, J=10.8 Hz), 3.14 (1 H, s), 2.66 (1 H,s), 2.58 (2 H, d, J=7.4 Hz), 2.22 (3 H, s), 1.81 (1 H, d, J=4.3 Hz),1.75 (1 H, d, J=7.2 Hz), 1.51-1.65 (2 H, m), 1.19 (3 H, s), 1.00 (3 H,d, J=7.2 Hz), 0.30 (3 H, t, J=7.7 Hz); MS (ESI) 486.1 [M+H]⁺.

More polar isomer: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.27 (2 H,m), 7.01-7.17 (4 H, m), 6.89-6.95 (1 H, m), 6.71 (1 H, dt, J=7.5, 1.3Hz), 5.81-5.93 (1 H, m), 5.17-5.25 (2 H, m), 4.32 (1 H, d, J=10.8 Hz),3.50 (1 H, br. s.), 3.23-3.32 (1 H, m), 3.06 (1 H, br. s.), 2.60-2.66 (2H, m), 2.13-2.20 (3 H, m), 1.91-2.01 (2 H, m), 1.64-1.70 (2 H, m),1.28-1.32 (3 H, m), 1.13 (3 H, d, J=7.0 Hz), 0.34 (3 H, t, J=7.5 Hz); MS(ESI) 486.1 [M+H]⁺.

Step E.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methylpiperidin-2-oneor(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methylpiperidin-2-one

To a solution of the less polar isomer prepared above in example 149,step D (96 mg, 0.20 mmol) in THF (2.0 mL) was added 1.4 Mmethylmagnesium bromide in toluene and THF (75:25) (423 μL, 0.592 mmol)at 0° C. Then the reaction was allowed to warm to rt and stirred forovernight. The reaction was quenched (sat NH₄Cl solution), extracted(2×EtOAc), and washed (brine). The combined organic layers were dried(Na₂SO₄) and concentrated under reduced pressure. Purification of theresidue by combi-flash (12 g SiO₂, 30% EtOAc/Hex) provided the titlecompound as a single isomer.

Step F.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methylpiperidin-2-oneor(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-5-hydroxy-4,5-dimethylhexan-3-yl)-3-methylpiperidin-2-one(Example 149, Step E) by a procedure similar to the one described inexample 129, Step D.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.01-7.27 (6 H, m), 6.96 (1 H, t,J=1.7 Hz), 6.70 (3 H, d, J=7.6 Hz), 4.59 (1 H, d, J=9.8 Hz), 3.63-3.91(1 H, m), 3.14 (1 H, s), 2.98 (1 H, d, J=14.5 Hz), 2.72 (1 H, d, J=14.5Hz), 1.98-2.21 (2 H, m), 1.84-1.96 (1 H, m), 1.56-1.69 (2 H, m), 1.48(3H, s), 1.15 (3 H, s), 1.06 (3 H, s), 0.75 (3 H, br. s.), 0.28 (3 H,br. s.); MS (ESI) 520.2 [M+H]⁺, 518.2 [M−H]⁻.

Example 1502-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-cyano-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. (2S)-methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

To a solution of (S)-methyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(1.06 g, 2.23 mmol; Example 91, Step A) and 4-methylmorpholine 4-oxide(393 mg, 3.35 mmol) in DCM (15.800 mL) was added osmium(VIII) oxidepolymer-bound, 1% DVB (56.8 mg, 2.234 μmol). After being vigorouslystirred at rt for 2 days, additional osmium(VIII) oxide polymer-bound,1% DVB (56.8 mg, 2.23 mmol) was added and the resulting solution wasvigorously stirred at rt for 2 days. The resin was filtered and washed(DCM). The combined organic layers were washed (sat. aq. NaCl solution),dried (Na₂SO₄), and concentrated under reduced pressure. Purification bychromatography on silica gel (SiO₂, 40 g, 53% and 63% EtOAc/Hexanes)provided the title compound.

Step B. (2S)-methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanoate

To a solution of (S)-methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)butanoateprepared above in Step A (749 mg, 1.47 mmol) in DCM (8.2 mL) was addedp-toluenesulfonic acid monohydrate (14.0 mg, 0.074 mmol) and2,2-dimethoxypropane (8.15 mL, 66.3 mmol). After being stirred at rt for3 h, the reaction mixture was concentrated under reduced pressure andthe residue was dissolved

(EtOAc and sat. aq. NaHCO₃) and extracted (3×EtOAc). The combinedorganic layers were washed (sat. aq. NaCl solution), dried (Na₂SO₄), andconcentrated under reduced pressure. Purification by chromatography onsilica gel (SiO₂, 40 g, 27% and 37% EtOAc/Hexanes) provided the titlecompound as a colorless film.

Step C.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

To a solution of (2S)-methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanoateprepared above in Step B (734 mg, 1.34 mmol) in ether (12.2 mL) wasadded lithium borohydride (58.3 mg, 2.68 mmol) at 0° C. After beingstirred at 0° C. for 30 min, the reaction was quenched (ice cold 10%citric acid), extracted (2×EtOAc) and washed (sat. aq. NaCl solution).The combined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure provided the title compound as a colorless film. Theproduct was used in the next step without further purification.

Step D.(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal

The title compound was prepared form(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 150, Step C) by a procedure similar to the one described inExample 91, Step C.

Step E.(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hex-2-enenitrile

To a solution of diethyl cyanomethylphosphonate (126 μL, 0.799 mmol) andDMPU (481 μL, 3.99 mmol) in THF (1.33 mL) was added 60% sodium hydridein mineral oil (24.0 mg, 0.599 mmol) at 0° C. The mixture was stirredfor 30 min, and then treated with a solution of(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanalprepared above in Step D (207 mg, 0.399 mmol) in THF (1.33 mL). Afterbeing stirred for 4 h, the reaction was quenched (water), extracted(2×EtOAc), and washed (sat. aq. NaCl solution). The combined organiclayers were dried (Na₂SO₄) and concentrated under reduced pressure.Purification of the residue by chromatography on silica gel (24 g SiO₂,30 to 40% EtOAc/Hex, gradient elution) provided the title compound as acolorless liquid.

Step F.(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hexanenitrile

To a solution of(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hex-2-enenitrileprepared above in Step E (208 mg, 0.384 mmol) in EtOH (12.8 mL) wasadded 10% palladium on activated carbon (40.9 mg, 0.038 mmol). Then thereaction mixture was subjected to regular hydrogenation with hydrogen(0.774 mg, 0.384 mmol). After being stirred at rt for 1.5 h, thecatalyst was filtered using a short plug of silica-gel and washed(EtOAc). The combined organic solutions were concentrated under reducedpressure. Purification by combi flash (flash column chromatography,Teledyne Isco, Lincoln, Nebr.) (SiO₂, 24 g, 35% and 40% EtOAc/Hexanes)provided the title compound as a colorless film.

Step G.(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexanenitrile

To a solution of(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)hexanenitrileprepared in Step F (120 mg, 0.221 mmol) in THF (1.10 mL) was added 2 Mlithium diisopropylamide (552 μL, 1.10 mmol) at −78° C. After beingstirred for 5 min at −78° C., iodomethane (94 μL, 1.51 mmol) was addedand the resulting solution was stirred at −78° C. for 30 min. Then thereaction was allowed to warm to rt and stirred for overnight. Thereaction was quenched (aq. sat. NH₄Cl) and extracted (2×EtOAc) and thecombined organic layers were wahsed (sat. aq. NaCl solution), dried(Na₂SO₄), and concentrated under reduced pressure. Purification bychromatography on silica gel (SiO₂, 30% and 40% EtOAc/hex) provided amixture of dimethylated product and monomethylated product, which wasresubecjected to the methylation conditions described below.

To a solution of the crude product from the previous reaction in THF(1.10 mL) was added 2 M lithium diisopropylamide inheptane/THF/ethylbenzene (552 μL, 1.10 mmol) at −78° C. After beingstirred for 5 min at −78° C., iodomethane (94 μL, 1.51 mmol) was addedand the resulting solution was stirred at −78° C. for 30 min. Then thereaction was allowed to warm to rt and stirred for overnight. Thereaction was quenched (aq. sat. NH₄Cl) and extracted (2×EtOAc) and thecombined organic layers were washed (sat. aq. NaCl solution), dried(Na₂SO₄), and concentrated under reduced pressure. Purification byRP-HPLC purification (60 to 90% MeCN/H₂O (0.1% TFA), gradient elution)provided the title compound.

Step H.(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexanenitrile

To a solution of(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexanenitrileprepared above in Step G (77 mg, 0.135 mmol) in THF (2.69 mL) was added3 N hydrochloric acid in water (1.35 μL, 4.04 mmol) at rt. After beingstirred at rt for 4 h, the reaction was diluted (sat. aq. NaCl) andextracted (2×EtOAc). The combined organic layers were washed (sat. aq.NaCl solution), dried (Na₂SO₄), and concentrated under reduced pressureto provide the title compound as a colorless foam.

Step I.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-5-cyano-5-methylhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(4S)-4-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)-2,2-dimethylhexanenitrileprepared above in Step H by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27 (2H, s), 7.00-7.20 (4 H, m),6.97 (1 H, t, J=1.7 Hz), 6.82 (1 H, dt, J=7.4, 1.4 Hz), 4.82 (1 H, d,J=10.6 Hz), 3.12 (1 H, s), 3.01 (1 H, d, J=15.1 Hz), 2.75 (3 H, d,J=15.1 Hz), 2.54 (1 H, s), 2.03-2.12 (1 H, m), 2.01 (1 H, s), 1.90 (1 H,dd, J=14.0, 2.6 Hz), 1.52 (3 H, s), 1.43 (3H, s), 1.35-1.41 (1 H, m),1.31 (3 H, s), 1.23 (1 H, d, J=13.9 Hz), 0.33 (3 H, t, J=7.3 Hz); MS(ESI) 515.0 [M+H]⁺, 513.0 [M−H]⁻.

Example 1512-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-2-oxopentan-3-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

To a solution of 1004 g (1.47 mol) of(3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 185, Step E) in THF (3.0 L) was added 2.50 L (2.50 mol) of a 1M solution of TBAF in THF over a 10 min period. The orange solution wasstirred at room temperature for 4 h. The reaction was quenched with 1 NHCl (3 L) and extracted with EtOAc (3×). The combined organic layerswere washed with a 3:1 mixture of water and saturated aqueous sodiumchloride (4×) and then saturated aqueous sodium chloride (1×). Theorganic layer was dried over Na₂SO₄, filtered and the filtrate wasconcentrated. Purification of the residue by chromatography (Biotage®Snap™ column; Biotage, LLC, Charlotte, N.C.), 10 to 50% EtOAc/hexanes,where the EtOAc contains 2% MeCN, gradient elution) provided the titlecompound as a white foam.

Step B.(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal

To a solution of 428 g (959 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 151, Step A) in dichloromethane (4.55 L) was added 25.9 mL(1.44 mol) of water. A solution of 610 g (1.44 mol) of Dess-Martinperiodinane in dichloromethane (4.55 L) was added slowly over a 25 minperiod so as to maintain an internal reaction temperature not exceeding25° C. The white slurry was stirred for 2.5 h and then was quenched bycautious, slow addition of saturated aqueous sodium thiosulfate (5.2 L)so as to maintain an internal reaction temperature below 30° C. Waterwas added and the mixture was extracted with dichloromethane (3×). Thecombined organic layers were washed with saturated aqueous sodiumbicarbonate solution (4×) and then saturated aqueous sodium chloride(1×), dried over Na₂SO₄, filtered and the filtrate was concentrated toafford a yellow oily solid. A mixture of ethyl ether and DCM were added,and precipitated solids were filtered off. The precipitation/filtrationprocess was repeated. The filtrate was concentrated to provide the titlecompound as a white solid. The crude product was used directly in thenext step.

Step C.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one

To a 0° C. solution of 399 g (899 mmol) of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 151, Step B) in THF (9 L) was added 1.93 L (2.70 mol) of a 1.4M solution of methylmagnesium bromide 75:25 in toluene/tetrahydrofuranslowly over a 30 min period so as to maintain an internal reactiontemperature below 6° C. The yellow solution was warmed to roomtemperature and stirred for 1.5 h. At this time the reaction was cooledto 0° C. and quenched by cautious, slow addition of saturated aqueousammonium chloride (4.6 L) so as to maintain an internal reactiontemperature below 15° C. The mixture was warmed to room temperature,ethyl acetate was added, and the layers were separated. The aqueouslayer was extracted with EtOAc (2×). The combined organic layers werewashed with water (1×) and then saturated aqueous sodium chloride (1×),dried over Na₂SO₄, filtered and the filtrate was concentrated to afforda yellow oil. Purification of the residue by chromatography on silica(Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.), 5% acetone/5%EtOAc/90% hexanes grading to 5% acetone/29% EtOAc/66% hexanes) providedthe title compound as a white solid.

Step D.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-2-oxopentan-3-yl)piperidin-3-yl)aceticacid

Ruthenium(III) chloride hydrate (1.404 g, 6.23 mmol) was added to asolution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one(Example 151, Step C) (130.30 g, 283 mmol) and NaIO₄ (61.5 g) in EtOAc(630 mL), CH₃CN (630 mL) and water (935 mL) at 18° C. The remainingNaIO₄ (307.5 g) was added in five portions over 2.5 hours whilemaintaining the temperature below 26° C. 15 minutes after the finaladdition of NaIO₄ the cooling bath was removed and the reaction mixturewas stirred at ambient temperature for 50 minutes. The tan reactionmixture was filtered using a Büchner funnel and washed with EtOAc (500mL) and CH₃CN (500 mL). The layers were separated and the aqueous layerwas extracted with EtOAc twice. The organics were pooled, washed with10% aq. NaHSO₃ (3×1 L), brine (1 L), dried (Na₂SO₄), decanted andconcentrated in vacuo to provide a green oil. The material was dissolvedin a minimum amount of DCM and purified using two 1.5 kg Biotage® Snap™columns (Biotage, LLC, Charlotte, N.C.) and eluting with 10-50% (15%MeOH/acetone)/hexanes to provide a light pink foam (109.67 g).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.25 (2 H, d, J=8.2 Hz), 6.93-7.18(5 H, m), 6.73-6.80 (1 H, m), 4.47 (1 H, d, J=10.6 Hz), 3.28 (1 H, ddd,J=13.4, 10.5, 3.0 Hz), 3.16 (1 H, dd, J=7.0, 5.5 Hz), 2.73-3.00 (2 H,m), 2.28-2.40 (1 H, m), 2.18-2.25 (1 H, m), 2.16 (3 H, s), 2.11-2.15 (1H, m), 1.83 (1 H, ddd, J=14.3, 7.8, 5.7 Hz), 1.47 (3 H, s), 0.64 (3 H,t, J=7.5 Hz); MS (ESI) 476.2 [M+H]⁺.

Example 1522-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of 3.86 g (8.13 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-2-oxopentan-3-yl)piperidin-3-yl)aceticacid (Example 151) in THF (102 mL) was added a 1 M solution of sodiumtri-sec-butylborohydride (N-Selectride®, Aldrich, St. Louis, Mo.) in THF(16.26 mL, 16.26 mmol) at −78° C. dropwise over a period of 5 min. Afterbeing stirred at −78° C. for 30 min, the reaction was allowed to warm tort. The reaction was stirred at rt for 2 h, the reaction was quenched(sat. NH₄Cl solution), extracted (3×EtOAc) and washed (3×ice-cold 1 Naq. HCl and 3×saturated aqueous sodium chloride). The combined organiclayers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. The crude material was purified bychromatography on a Biotage Isolera flash purification system (Biotage,Charlotte, N.C.) (2×1500 g columns, using a gradient from 10-30% (15%MeOH/acetone) in hexanes. The purified material was then recrystallizedfrom 3:1 hexane/acetone (8 mL/g) to provide the title compound.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.30 (t, J=7.6 Hz, 3 H), 1.00 (d, J=6.3Hz, 3 H), 1.26 (s, 3 H), 1.41-1.49 (m, 1 H), 1.55-1.64 (m, 1 H),2.04-2.15 (m, 2 H), 2.29-2.33 (m, 1 H), 2.48 (d, J=13.7 Hz, 1 H), 2.87(d, J=13.7 Hz, 1 H), 3.35-3.40 (m, 1 H), 4.01-4.06 (m, 1 H), 4.77 (d,J=10.9 Hz, 1 H), 4.80 (br. s, 1 H), 6.93-6.95 (m, 1 H), 7.08-7.10 (m, 1H), 7.17-7.27 (m, 4 H), 7.33 (d, J=8.4 Hz, 2 H), 12.42 (br s, 1 H); MS(ESI) 478.2 [M+H]⁺, 476.2 [M−H]⁻. [α]_(D)=+110° (T=23° C., MeOH,c=0.51).

Alternatively the title compound can be prepared from(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-oneas prepared in Example 261 step F.

To a 10 mL round-bottom reaction flask was added(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one(750 mg, 1.998 mmol), (2S,3S)-3-aminopentan-2-ol hydrochloride (837 mg,6.00 mmol, reference: J. Org. Chem., 2003, 68 (26), 9948), andtriethylamine (1966 μl, 13.99 mmol). The vessel was fitted with a refluxcondensor and heated to 85 to 95° C. for 2 d. The reaction was cooled toRT and diluted with ethyl acetate and washed with 1N HCl (2×20 mL) andbrine. The organic layer was dried over MgSO₄, filtered, andconcentrated. Purification by column chromatography using 40 to 50%ethyl acetate in hexanes afforded(S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide.

¹H NMR (500 MHz, DMSO-d6) δ 7.17 (m, 2H), 7.16 (m, 1H), 7.14-7.08(series of m, 2H), 6.97 (m, 2H), 6.88 (br d, J=6.9 Hz, 1H), 5.96 (d,J=8.3 Hz, 1H), 5.65 (ddt, J=17.4, 10.2, 7.2 Hz, 1H), 5.07 (dd J=10.3,1.0 Hz, 1H), 5.02 (d, J=17.6, 1H), 4.75 (t, J=4.2 Hz, 1H), 3.79 (m, 1H),3.66 (ddd, J=8.8, 5.9, 4.2 Hz, 1H), 3.30 (d, J=3.4 Hz, 1H), 3.03 (dt,J=6.9, 5.4 Hz, 1H), 2.37 (dd, J=13.9, 7.3 Hz, 1H), 2.32 (dd, J=14.7, 5.6Hz, 1H), 2.12 (dd, J=13.7, 7.1 Hz, 1H), 2.01 (d, J=4.7 Hz, 1H), 1.83(dd, J=14.7, 7.3 Hz, 1H), 1.58 (m, 1H), 1.42 (ddq, J=14.9, 8.6, 7.3 Hz),1.14 (s, 3H), 1.14 (d, J=6.4 Hz, 3H), 0.90 (t, J=7.3 Hz, 3H) ppm. LC/MS(M+H)=478.2.

To a solution of(S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N-((2S,3S)-2-hydroxypentan-3-yl)-2-methylpent-4-enamide(127 mg, 0.265 mmol) in toluene (5309 μl) was added ammonium molybdate((NH₄)₂MoO₄) (5.20 mg, 0.027 mmol) and heated to reflux under Dean-Starkconditions overnight. The reaction was cooled to room temperature,diluted with ethyl acetate and washed with sat. NaHCO₃ and brine. Theorganics were dried over MgSO₄, filtered and concentrated. Purificationby column chromatography using 20 to 40% ethyl acetate in hexanesafforded(1R,2R,4S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-4-((4S,5S)-4-ethyl-5-methyl-4,5-dihydrooxazol-2-yl)-4-methylhept-6-en-1-ol.

¹H NMR (500 MHz, DMSO-d6) δ 7.25 (m, 2H), 7.12 (m, 2H), 7.07 (br s, 1H),7.05 (m, 2H), 6.96 (br d, J=6.8 Hz, 1H), 5.53 (ddt, J=17.4, 10.3, 7.4Hz, 1H), 5.42 (d, J=4.2 Hz, 1H), 4.95 (m, 2H), 4.66 (t, J=4.9 Hz, 1H),3.56 (dq, J=7.6, 6.1 Hz, 1H), 3.12 (q, J=7.1 Hz, 1H), 2.90 (ddd, (9.5,5.1, 2.3 Hz, 1H), 2.20 (m, 2H), 1.93 (dd, J=13.7, 7.8 Hz, 1H), 1.75 (dd,J=14.3, 2.2 Hz, 1H), 1.11 (m, 1H), 1.10 (d, J=6.4 Hz, 3H), 0.98 (m, 1H),0.97 (s, 3H), 0.75 (t, J=7.6 Hz, 3H) ppm. LC/MS (M+H)=460.2.

To a solution of(1R,2R,4S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)-4-((4S,5S)-4-ethyl-5-methyl-4,5-dihydrooxazol-2-yl)-4-methylhept-6-en-1-ol(80 mg, 0.174 mmol) in CH₂Cl₂ (1737 μl) at −50° C. was added2,6-lutidine (46.4 μl, 0.400 mmol) followed by trifluoromethanesulfonicanhydride solution, 1 M in methylene chloride (191 μl, 0.191 mmol). Thereaction was stirred at −50° C. for 30 min and then treated with anadditional 25 uL of trifluoromethanesulfonic anhydride solution, 1 M inmethylene chloride, then 2 mL of sat. CuSO₄. The reaction was warmed tort and extracted with dichloromethane. The organic phase was dried overMgSO₄, filtered and concentrated. Purification by column chromatographyusing 40 to 80% acetone in hexanes afforded(2S,3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtriflate.

¹H NMR (500 MHz, DMSO-d6) δ 7.55-7.05 (series of m, 8H), 5.88 (ddt,J=17.3, 10.0, 7.8 Hz, 1H), 5.36 (dd, J=17.1, 2.0 Hz, 1H), 5.31 (d,J=10.8 Hz, 1H), 5.28 (dd, J=10.0, 2.0 Hz, 1H), 5.18 (quintet, J=6.1 Hz,1H), 4.10 (td, J=6.6, 2.7 Hz, 1H), 3.98 (ddd, J=13.7, 11.2, 3.4 Hz, 1H),2.80 (ABX, J_(AB)=13.7 Hz, J_(AX)=7.3 Hz, 1H), 2.73 (ABX J_(AB)=13.7 Hz,J_(BX)=7.8 Hz, 1H), 2.49 (m, 1H), 2.41 (t, J=13.7 Hz, 1H), 2.00 (dd,J=13.9, 3.7 Hz, 1H), 1.55 (d, J=6.1 Hz, 1H), 1.31 (s, 3H), 0.95 (dqd,J=14.2, 7.8, 3.0 Hz, 1H), 0.58 (t, J=7.3 Hz, 1H), 0.47 (ddq, J=13.7,6.3, 6.3 Hz, 1H) ppm. LC/MS (M+=442.2).

To a solution of(2S,3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtriflate (60 mg, 0.101 mmol) in 1 mL dichloromethane at 0° C. was addedtetra-n-butylammonium chloride (2.81 mg, 10.13 μmol) and acetic acid(116 μl, 2.025 mmol). To this was added KMnO₄ (32.0 mg, 0.203 mmol) in 1mL water followed by a 1 mL water rinse. An additional 10 eq. aceticacid were added followed by an additional 16 mg KMnO₄ in 1 mL water.This was repeated once more. A total of 4 eq KMnO₄ and 40 eq. aceticacid were added.

The reaction was quenched with 1 mL of sat. Na₂S₂O₃ solution and dilutedwith ethyl acetate. The layers were separated and the organic phase waswashed once with brine, dried over MgSO₄, filtered and concentrated toafford crude(2S,3S,5S,6R,7aR)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dimethylhexahydrofuro[2,3-a]oxazolo[3,2-a]pyridin-9(5H)-one.This crude residue was redissolved in 2 mL isopropyl acetate and treatedwith 2 mL sat. NaHCO₃ and heated to 70° C. After 2 h, the reaction wascooled to 0° C. and treated with 10% acetic acid to a pH of about 3. Thereaction was diluted with ethyl acetate and washed once with 10% aceticacid solution, dried over MgSO₄, filtered, and concentrated.Purification by column chromatography using 10 to 50% of (15%MeOH/acetone) in hexanes afforded2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Example 1532-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate

To a solution of 260 mg (0.543 mmol) of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 152) in 5 mL of THF was added 60% sodium hydride (217 mg,5.43 mmol) at 0° C. After being stirred at 0° C. for 20 min, iodomethane(271 uL, 4.35 mmol) was added. The reaction was allowed to warm toambient temperature, and stirred for an additional 3 h until completion.The reaction was quenched with saturated aqueous NH₄Cl solution,extracted with EtOAc (2×25 mL). The combined organic layers were washedwith saturated NaCl, dried over MgSO₄, filtered and the filtrate wasconcentrated to provide the title compound.

Step B. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate

To a solution of 50 mg (0.102 mmol) of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 153, Step A) in 0.3 mL of DMF was added 60% sodium hydride(20.31 mg, 0.508 mmol) at 25° C. After being stirred at 25° C. for 20min, iodomethane (25.4 uL, 0.406 mmol) was added. The reaction wasstirred for an additional 30 min and was quenched with saturated aqueousNH₄Cl solution, extracted with EtOAc (2×25 mL). The combined organiclayers were washed with saturated NaCl, dried over MgSO₄, filtered andthe filtrate was concentrated. Purification of the residue by flashchromatography on silica gel (eluent: 20 to 60% EtOAc/hexanes) providedthe title compound.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-methoxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(34 mg, 0.067 mmol; Example 153, Step B) in THF/MeOH/H₂O (1/1/1, 0.48mL) was added 2 M lithium hydroxide (67 uL, 0.134 mmol) at rt. Afterbeing stirred at rt for 4 h, the reaction was quenched saturated aqueousNH₄Cl and extracted (2×DCM) and the combined organic layers were washed(1×sat. aq. NaCl solution) and concentrated under the reduced pressure.Purification of the residue by flash chromatography on silica gel(eluent: 70 to 100% EtOAc/hexanes) provided the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.38 (t, J=8.0 Hz, 3 H), 1.05 (d,J=4.0 Hz, 1 H), 1.48 (s, 3 H), 1.65 (m, 1 H), 1.75 (m, 1 H), 2.00 (dd,J=12.0, 4 Hz, 1 H), 2.21 (m, 1 H), 2.48 (m, 1 H), 2.70 (d, J=16.0 Hz, 1H), 3.06-3.15 (m, 2 H), 3.41 (s, 3 H), 3.94 (m, 1 H), 4.63 (d, J=12.0Hz, 1 H), 6.75 (d, J=8.0 Hz, 1 H), 6.90-7.05 (m, 3 H), 7.05-7.15 (m, 2H), 7.25 (d, J=8.0 Hz, 2 H); MS (ESI) 492.1 [M+H]⁺.

Example 1542-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

A solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid (71 mg, 0.154 mmol) (Example 210, StepA) in THF (2 mL) was spargedwith argon for 5 minutes. The mixture was cooled to 0° C. andmethylmagnesium chloride, 3.0 M solution in tetrahydrofuran (0.113 ml,0.339 mmol) was added at such a rate that the internal temperature didnot get above 4° C. The mixture was stirred at 0° C. for 45 minutes. Themixture was quenched with sat. aq. NH₄Cl solution and extracted withEtOAc. The combined organic layers were dried over Na₂SO₄, filtered andthe filtrate was concentrated. The residue was purified by flashchromatography on silica gel (2×4 g stacked columns, eluent: 5 to 15%isopropanol/hexanes) to give the title compound as the more polardiastereomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J=7.63 Hz, 3 H), 1.18 (d,J=6.65 Hz, 3 H), 1.44 (s, 3 H), 1.63-1.77 (m, 1 H), 1.99-2.18 (m, 3 H),2.61-2.71 (m, 1 H), 2.81 (d, J=14.28 Hz, 1 H), 2.92 (d, J=14.48 Hz, 1H), 3.24 (td, J=10.22, 5.77 Hz, 1 H), 4.11-4.22 (m, 1 H), 4.45 (d,J=10.17 Hz, 1 H), 6.74 (dt, J=7.53, 1.61 Hz, 1 H), 6.93-7.05 (m, 3 H),7.07-7.14 (m, 1 H), 7.15-7.20 (m, 1 H), 7.24-7.31 (m, 2 H). MassSpectrum (ESI) m/e=478.1 (M+1).

Example 1552-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3R)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Isomer 1)

Step A.(R)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-oneby a procedure similar to the one described in Example 91, Step B. Theproduct was used in the next step without further purification.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3R)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one

The title compound was prepared from(R)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 155, Step A) as described in Example 149, Step A. Purificationby flash chromatography (SiO₂, 40 g, 10% to 25% EtOAc/hexanes) providedthe title compound as a mixture of two diastereomers at the newly formedstereocenter.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-2-oxopentan-3-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3R)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one(0.210 g, 0.456 mmol; Example 155, Step B) by a procedure similar to theone described in Example 71, Step F.

Step D.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3R)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-2-oxopentan-3-yl)piperidin-3-yl)aceticacid (0.150 g, 0.315 mmol, Example 155, Step C) in THF/MeOH (3/1, 4 mL)was added sodium borohydride (0.060 g, 1.574 mmol) at room temperature.After being stirred at room temperature for 1 h, the reaction wasacidified with sat. aq. NH₄Cl solution and extracted with EtOAc. Thecombined organic layers were washed with sat. aq. NaCl solution, driedover MgSO₄, filtered and the filtrate was concentrated under reducedpressure. The crude material was purified by reversed phase preparatoryHPLC (eluent: 10-90% acetonitrile, water, 0.1% TFA, gradient elution) togive a mixture of two isomers (dr=93:7). Individual stereoisomers wereseparated by chiral HPLC (250×30 mm CHIRALPAK® IC column (CHIRALTECHNOLOGIES, INC., West Chester, Pa., USA) with 46 g/minispropylamine+(20 μM NH₃)+84 g/min CO₂ on Thar 350 SFC (TharTechnologies, Inc., Pittsburgh, Pa.)) to give the title compound as thefaster eluting stereoisomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.61 (d, J=6.65 Hz, 3 H), 0.99-1.08(t, J=7.34 Hz, 3 H), 1.18-1.37 (m, 1 H), 1.45-1.60 (m, 4 H), 1.99-2.21(m, 3 H), 2.69 (dd, J=11.15, 3.72 Hz, 1 H), 2.82-2.90 (m, 1 H),3.18-3.30 (m, 1 H), 3.69-3.79 (m, 1 H), 4.34 (d, J=10.56 Hz, 1 H), 6.71(d, J=7.63 Hz, 1 H), 6.88-7.04 (m, 2 H), 7.04-7.20 (m, 3 H), 7.20-7.32(m, 2 H). MS (ESI) 478.0 [M+H]⁺.

Further elution provided Example 156.

Example 1562-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3R)-2-hydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Example 155, Step D; slower eluting isomer from chiral HPLC.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.81 (d, J=6.46 Hz, 3 H), 1.01 (t,J=7.43 Hz, 3 H), 1.47 (s, 3 H), 1.64 (m, 1 H), 1.82-1.95 (m, 1 H),2.13-2.25 (m, 2 H), 2.73-2.84 (m, 2 H), 2.93 (d, J=14.87 Hz, 1 H), 3.37(m, 1H), 3.93 (m, 1 H), 4.45 (d, J=10.56 Hz, 1 H), 6.72 (d, J=7.43 Hz, 1H), 6.96 (m, 1 H), 7.02-7.17 (m, 4 H), 7.21 (m, 2 H); Mass Spectrum(ESI) m/z=478.0 (M+1).

Example 1572-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-2-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-2-methylpentan-3-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one(0.100 g, 0.218 mmol; Example 149, Step B) in THF (4 mL) was added asolution of methylmagnesium bromide, 1.4M in toluene (0.104 g, 0.873mmol) at 0° C. The reaction was allowed to warm to room temperature.After being stirred at room temperature for 4 h, another 1 eq. of MeMgBrwas added and stirred for another 2 h. The reaction was quenched w/satNH₄Cl solution, and extracted with EtOAc. The combined organic layerswere washed with sat. aq. NaCl solution, dried over MgSO₄, filtered andthe filtrate was concentrated under reduced pressure. The crude materialwas absorbed onto a plug of silica gel and purified by chromatography onsilica gel, eluting with 40% EtOAc/hexanes, to provide the titlecompound as a light-yellow oil.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-2-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-2-methylpentan-3-yl)-3-methylpiperidin-2-one(Example 157, Step A) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.37 (t, J=7.63 Hz, 3 H) 1.10 (s, 3H) 1.35 (s, 3 H) 1.50 (s, 3 H) 1.68 (ddd, J=15.21, 7.78, 4.01 Hz, 1 H)2.10-2.31 (m, 3 H) 2.44-2.55 (m, 1 H) 2.78-2.95 (m, 2 H) 3.24-3.37 (m, 1H) 4.40 (d, J=10.56 Hz, 1 H) 6.73 (dt, J=7.53, 1.52 Hz, 1 H) 6.95 (m, 1H) 7.01-7.21 (m, 4 H) 7.21-7.38 (m, 2 H). MS (ESI) 492.2 [M+H]⁺.

Example 1582-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4S)-4-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S,4R)-4-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-4-hydroxyhexan-3-yl)-3-methylpiperidin-2-one

The title compound was prepared from(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 91, Step C) and ethylmagnesium bromide as described in Example149, Step A. The crude material was used in the next step withoutfurther purification

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-4-oxohexan-3-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-4-hydroxyhexan-3-yl)-3-methylpiperidin-2-one(Example 158, Step A) as described in Example 71, Step F.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydroxyhexan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-4-oxohexan-3-yl)piperidin-3-yl)aceticacid (0.038 g, 0.077 mmol; Example 158, Step B) in a mixture of THF andmethanol (4:1, 5 mL) was added sodium borohydride (9 mg, 0.24 mmol) at0° C. Then the reaction was allowed to warm to room temperature. Afterbeing stirred at room temperature for 1.5 h, another 2 eq. of sodiumborohydride were added and stirred for another 0.5 h. The reaction wasacidified (10% citric acid) and extracted (2×EtOAc). The combinedorganic layers were washed (sat. aq. NaCl solution), dried (MgSO₄), andconcentrated under reduced pressure. The crude material was purified byreverse phase preparatory HPLC (eluent: 10 to 90% acetonitrile, water,0.1% TFA, gradient elution) to give the title compound as the firsteluting fraction as a white solid after lyophilization.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J=7.53 Hz, 3 H) 0.91 (t,J=7.34 Hz, 3 H) 1.38 (m, 1 H) 1.44 (s, 3 H) 1.54 (m, 1 H) 1.72 (m, 1 H)2.00-2.25 (m, 3 H) 2.73-2.79 (m, 1 H) 2.82 (d, J=14.48 Hz, 1 H) 2.92 (d,J=14.48 Hz, 1 H) 3.26 (m, 1 H) 3.87-3.93 (m, 1 H) 4.43 (d, J=10.17 Hz, 1H) 6.75 (dt, J=7.53, 1.52 Hz, 1 H) 6.95-7.07 (m, 3 H) 7.12 (t, J=7.73Hz, 1 H) 7.17 (m, 1 H) 7.25-7.35 (m, 2 H). MS (ESI) 492.2 [M+H]⁺.

Example 1592-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-3-methylpiperidin-2-one

To a solution of 50 mg (0.112 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 91, Step B) in 0.5 mL of THF was added 60% sodium hydride (8.96mg, 0.244 mmol) at 0° C. After being stirred at 0° C. for 30 min,iodomethane (14.01 uL, 0.244 mmol) was added. The reaction was allowedto warm to 25° C., and stirred for an additional 2 h until completion.The reaction was quenched with saturated aqueous NH₄Cl solution,extracted with EtOAc (2×25 mL). The combined organic layers were washedwith saturated NaCl solution, dried over MgSO₄, filtered and thefiltrate was concentrated to provide the title compound.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-methoxybutan-2-yl)-3-methylpiperidin-2-one(Example 159, Step A) by a procedure similar to the one described inExample 71, Step F. The residue was purified by reverse phasepreparatory HPLC (MeCN in water with 0.1% TFA, gradient elution) to givethe title compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, J=8.0 Hz, 3 H), 1.42 (s, 3H), 1.50 (m, 1 H), 1.93 (m, 1 H), 2.02 (dd, J=12.0, 4.0 Hz, 1 H), 2.18(dd, J=12.0, 12.0 Hz, 1 H), 2.71 (d, J=16.0 Hz, 1 H), 3.05 (d, J=12.0Hz, 1 H), 2.90-3.10 (m, 2 H), 3.31 (dd, J=8.0, 4.0 Hz, 1 H), 3.38 (s, 3H), 3.93 (t, J=12.0 Hz, 1 H), 4.61 (d, J=8.0 Hz, 1 H), 6.78 (d, J=8.0Hz, 1 H), 7.01 (d, J=8.0 Hz, 2 H), 7.05 (s, 1 H), 7.12 (t, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1 H), 7.26 (d, J=8.0 Hz, 2 H); MS (ESI) 478.0[M+H]⁺.

Example 1602-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-2-one

A solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one(30 mg, 0.065 mmol; Example 149, Step B) andtrimethyl(trifluoromethyl)silane (48.5 μL, 0.327 mmol) in THF (0.5 mL)was treated with 1 M tetrabutylammonium fluoride solution in THF (196μL, 0.196 mmol) at 0° C. After being stirred for 2 h, the reactionmixture was extracted with EtOAc. The combined organic layers werewashed with water and saturated NaCl solution, dried over Na₂SO₄,filtered and the filtrate was concentrated. The residue was purified bythe flash chromatography on silica gel (eluent: 10 to 20% EtOAc/Hexane,gradient elution) to provide the title compound as the major product.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((3S)-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-1,1,1-trifluoro-2-hydroxy-2-methylpentan-3-yl)piperidin-2-one(Example 160, Step A) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.33 (t, J=8.0 Hz, 3 H), 1.47 (s, 3H), 1.52 (s, 3 H), 1.70 (m, 1 H), 2.10-2.25 (m, 3 H), 2.89 (d, J=8.0 Hz,2 H), 2.95 (t, J=8.0, 1 H), 3.43 (m, 1 H), 4.40 (d, J=12.0 Hz, 1 H),6.75 (d, J=8.0 Hz, 1 H), 6.95 (m, 1 H), 7.08-7.20 (m, 3 H), 7.26-7.40(m, 3 H); MS (ESI) 545.2 [M+H]⁺.

Example 1612-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropane sulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetamide

A solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (0.055 g, 0.095 mmol; Example 141) in DMF (2.0 mL) was treated withHBTU (0.072 g, 0.189 mmol),N¹-((ethylimino)methylene)-N³,N³-dimethylpropane-1,3-diaminehydrochloride (0.036 g, 0.189 mmol) and sodium hydrogencarbonate (0.016g, 0.189 mmol) successively. Let it stir for 0.5 h. 7.0M ammonia inmethanol (0.135 mL, 0.946 mmol) was added dropwise. After being stirredat room temperature for 18 h, the reaction was diluted with water,extracted (2×EtOAc), and washed (1×saturated NaHCO₃, and 2×sat. aq. NaClsolution). The combined organic layers were dried over Na₂SO₄, filteredand the filtrate was concentrated under reduced pressure. The residuewas purified by reverse phase preparatory HPLC (eluent: 10 to 90%acetonitrile, water, 0.1% TFA, gradient elution) to give the titlecompound as a white solid after lyophilization.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.52 (t, J=7.53 Hz, 3 H) 0.97-1.07(m, 2 H) 1.18-1.25 (m, 2 H) 1.47 (s, 3 H) 1.59-1.62 (m, 1 H) 1.84-2.06(m, 2 H) 2.33 (ddd, J=8.02, 4.79, 3.23 Hz, 1 H) 2.43 (t, J=13.8 Hz, 1 H)2.65-2.80 (m, 2 H) 2.81-2.95 (m, 5 H) 3.17 (ddd, J=13.74, 10.91, 2.93Hz, 1 H) 4.80 (d, J=10.76 Hz, 1 H) 6.78 (br. s., 1 H) 6.86-6.90 (m, 1 H)6.97-7.01 (m, 1 H) 7.10-7.15 (m, 2 H) 7.24 (d, J=7.82 Hz, 4 H) 7.42 (br.s., 1 H); Mass Spectrum (ESI) m/z=580.2 (M+1).

Example 1622-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(methylsulfonyl)acetamide

A solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (0.045 g, 0.077 mmol) (Example 141) in THF (2.0 mL) was treatedwith methanesulfonamide (0.029 g, 0.310 mmol),N-ethyl-N-isopropylpropan-2-amine (0.050 g, 0.387 mmol) and1,1′-carbonyldiimidazole (0.050 g, 0.310 mmol), successively. Themixture was heated to reflux for 48 h, quenched with sat. NH₄Cl solutionand extracted with EtOAc. The combined organic layers were dried overMgSO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by reverse phase preparatory HPLC(eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) togive the title compound as a white solid after lyophilization.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.52 (t, J=7.53 Hz, 3 H) 0.96-1.08(m, 2 H) 1.15-1.28 (m, 2 H) 1.50 (s, 3 H) 1.61 (ddd, J=14.33, 7.68, 3.62Hz, 1 H) 1.92 (dd, J=13.69, 2.93 Hz, 1 H) 1.96-2.10 (m, 1 H) 2.34 (tt,J=8.02, 4.79 Hz, 1 H) 2.49 (t, J=13.89 Hz, 1 H) 2.65 (d, J=14.87 Hz, 1H) 2.73 (dd, J=14.48, 2.35 Hz, 1 H) 2.87 (s, 3 H) 2.98-3.08 (m, 2 H)3.32 (s, 3 H) 4.79 (d, J=10.56 Hz, 1 H) 6.84-6.90 (m, 1 H) 6.94-7.07 (m,1 H) 7.08-7.16 (m, 2 H) 7.19-7.32 (m, 4 H)

Examples 163-170 were prepared from2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (Example 141) by using the following general procedure using theappropriate amine, unless noted otherwise.

A mixture of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (0.020 g, 0.034 mmol; Example 141), corresponding amine (1.2 eq.),N-ethyl-N-isopropylpropan-2-amine (3.3 eq.) and(1H-benzo[d][1,2,3]triazol-1-yloxy)tripyrrolidin-1-ylphosphoniumhexafluorophosphate (V) (1.05 eq.) in 2 ml of DCM was stirred at roomtemperature for 5 h. The solvent was removed under reduced pressure, andthe residue was purified by reverse phase HPLC (40-90%water/acetonitrile gradient with 0.1% TFA). Desired fractions were thencollected and concentrated to give pure product.

Example R Amine used 163

3-Aminopropan-1-ol 164

2-Aminoethanol 165

Hydroxylamine 166

O-Methylhydroxylamine 167

(R)-3-Aminopropane-1,2-diol 168

(S)-3-Aminopropane-1,2-diol 169

Monosodium cyanamide 170

N¹,N¹-Dimethylethane-1,2-diamine

Example 1632-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3-hydroxypropyl)acetamide

¹H NMR (400 MHz, MeOH-d₄) δ ppm 0.54 (t, J=7.63 Hz, 3 H), 1.00-1.19 (m,4 H), 1.39 (s, 3 H), 1.65-2.13 (m, 5 H), 2.25-2.36 (m, 1H), 2.48-2.61(m, 2 H), 2.81-2.95 (m, 6 H), 3.25-3.43 (m, 3 H), 3.61 (t, J=6.26 Hz, 1H), 4.13-4.26 (br, 1 H), 4.44 (s, 1H), 4.82 (d, J=10.76 Hz, 1 H),6.97-7.07 (m, 2 H), 7.11-7.22 (m, 4 H), 7.27-7.347 (m, 2 H). MassSpectrum (ESI) m/z=638.2 (M+1).

Example 1642-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-hydroxyethyl)acetamide

¹H NMR (400 MHz, MeOH-d₄) δ ppm 0.51 (t, J=7.53 Hz, 3 H), 0.95-1.15 (m,4H), 1.38 (s, 3H), 1.60-1.74 (m, 1H), 1.79-1.92 (m, 1 H), 2.02-2.11 (m,1 H), 2.22-2.33 (m, 1 H), 2.49-2.58 (m, 2H), 2.78-2.93 (m, 6 H),3.37-3.39 (m, 2 H), 3.53-3.64 (m, 2 H), 4.10-4.24 (m, 1 H), 4.39-4.49(m, 1 H), 4.79 (d, J=10.76 Hz, 1H), 6.95-7.05 (m, 2 H), 7.10-7.21 (m, 4H), 7.24-7.32 (m, 2 H). Mass Spectrum (ESI) m/z=624.4 (M+1).

Example 1652-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-hydroxyacetamide

¹H NMR (400 MHz, MeOH-d₄) δ ppm 0.53 (t, J=7.53 Hz, 3 H), 1.00-1.16 (m,4 H), 1.38 (s, 3 H), 1.70 (ddd, J=14.23, 7.78, 4.21 Hz, 1 H), 1.88 (ddd,J=14.28, 8.51, 7.34 Hz, 1 H), 2.09-2.16 (m, 1 H), 2.17-2.22 (m, 1 H),2.24-2.39 (m, 2 H), 2.52-2.60 (m, 1 H), 2.77-2.88 (m, 2 H), 2.92 (s, 3H), 3.37-3.44 (m, 1 H), 4.20 (br 1 H), 4.82 (d, J=10.76 Hz, 1 H),7.01-7.09 (m, 2 H), 7.13-7.22 (m, 4 H), 7.30 (d, J=8.02 Hz, 2 H). MassSpectrum (ESI) m/z=618 (M+1).

Example 1662-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-methoxyacetamide

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, J=7.53 Hz, 3 H), 0.96-1.07(m, 2 H), 1.17-1.28 (m, 2 H), 1.43 (s, 3 H), 1.55-1.65 (m, 1 H),1.87-2.00 (m, 1 H), 2.07-2.13 (dd, J=13.79, 2.64 Hz, 1 H), 2.28-2.42 (m,2 H), 2.63-2.77 (m, 3 H), 2.88 (br, 4 H), 3.26 (ddd, J=13.89, 10.66,3.03 Hz, 1H), 3.82 (s, 3 H), 4.25 (br, 1 H), 4.77 (d, J=10.76 Hz, 1 H),6.88-6.92 (m, 1 H), 6.99-7.05 (m, 2 H), 7.10-7.14 (m, 2 H), 7.18-7.30(m, 3 H). Mass Spectrum (ESI) m/z=632 (M+1).

Example 1672-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N#R)-2,3-dihydroxypropyl)acetamide

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.51 (t, J=6.6 Hz, 3 H), 1.01 (t,J=8.3 Hz, 2H), 1.21 (br. s., 2H), 1.40-1.48 (m, 3 H), 1.58 (dd, J=7.8,3.9 Hz, 1 H), 1.81-1.99 (m, 2 H), 2.28-2.36 (m, 1 H), 2.37-2.49 (m, 1H), 2.52-2.64 (m, 1 H,), 2.67-2.77 (m, 1 H), 2.84 (br. s., 2 H), 2.88(s, 4 H), 2.90-3.05 (m, 7 H), 3.11-3.23 (m, 2 H), 3.47 (br. s., 2 H),3.55-3.72 (m, 2 H), 3.89 (br. s., 1H), 4.25 (br. s., 1 H), 4.76 (d,J=10.3 Hz, 1 H), 6.85-6.92 (m, 1 H) 6.98 (br. s., 2 H), 7.00-7.06 (m, 1H), 7.13 (br. s., 3 H), 7.20-7.26 (m, 2 H).

Example 1682-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N—((S)-2,3-dihydroxypropyl)acetamide

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.43-0.58 (m, 3 H), 1.01 (t, J=7.6Hz, 2 H), 1.16-1.24 (m, 2 H), 1.41-1.45 (m, 1 H), 1.45-1.49 (m, 2 H),1.49 (s, 1 H), 1.54-1.66 (m, 1 H), 1.79-1.95 (m, 2 H), 2.28-2.36 (m, 1H), 2.38-2.49 (m, 1 H), 2.55 (d, J=13.7 Hz, 1 H), 2.72 (s, 5 H), 2.74(s, 4 H,), 2.84 (d, J=13.2 Hz, 2 H), 2.88 (s, 3 H), 3.11-3.25 (m, 2 H),3.28-3.39 (m, 1 H), 3.51-3.59 (m, 1 H), 3.59-3.76 (m, 2 H), 3.92 (br.s., 1 H), 4.18-4.31 (m, 1 H), 4.70-4.81 (m, 1 H), 6.90 (d, J=5.1 Hz, 1H) 6.92-7.01 (m, 2 H,), 7.10-7.16 (m, 2 H), 7.20-7.26 (m, 2 H).

Example 1692-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-cyanoacetamide

A mixture of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (0.030 g, 0.052 mmol; Example 141), N,N′-dicyclohexylcarbodiimide(10.64 mg, 0.052 mmol) and N-hydroxysuccinimide (5.94 mg, 0.052 mmol) in3 mL of THF was stirred while cooling with an ice bath for 3 h. Thereaction mixture was filtered and the filtrate was added dropwise to asolution of monosodium cyanamide (10.90 mg, 0.170 mmol) in 2 mL of waterat an ice bath temperature. The reaction mixture was stirred at roomtemperature for 12 h. Solvents were removed and the residue was purifiedby reverse phase HPLC (40 to 90% water/acetonitrile gradient with 0.1%TFA). Desired fractions were then collected and concentrated to give thetitle compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.52 (t, J=7.6 Hz, 3 H), 0.98-1.10(m, 2 H), 1.17-1.30 (m, 2 H), 1.49-1.53 (m, 3 H), 1.54-1.61 (m, 1 H),1.91-2.03 (m, 1 H), 2.35 (tt, J=8.0, 4.7 Hz, 1 H), 2.56 (t, J=13.8 Hz, 1H), 2.60-2.66 (m, 1 H), 2.71-2.77 (m, 1 H), 2.80-2.87 (m, 1 H),2.87-2.91 (m, 3 H), 2.91-3.01 (m, 1 H), 3.18 (d, J=16.1 Hz, 1 H),4.19-4.32 (m, 1 H), 4.79 (d, J=10.8 Hz, 1 H), 6.84 (dt, J=7.1, 1.6 Hz, 1H), 6.92-6.96 (m, 1 H), 7.11-7.18 (m, 2 H), 11.77 (br. s., 1 H).

Example 1702-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(2-(dimethylamino)ethyl)acetamide

¹H NMR (400 MHz, MeOH-d₄) δ ppm 0.52 (t, J=7.53 Hz, 3 H), 1.01-1.21 (m,4 H), 1.47 (s, 3 H) 1.62-1.85 (m, 2 H), 1.90 (dd, J=13.50, 3.13 Hz, 1H), 2.42 (t, J=13.69 Hz, 1 H), 2.51-2.62 (m, 2 H), 2.80-2.91 (m, 3 H,2.93 (s, 3 H), 3.03 (s, 6 H), 3.38-3.50 (m, 2 H), 3.29-3.39 (m, 2H),3.84 (ddd, J=15.01, 7.38, 4.79 Hz, 1 H), 4.21 (dd, J=13.89, 10.56 Hz, 1H), 4.80 (d, J=10.76 Hz, 1 H), 7.00-7.12 (m, 2 H) 7.15-7.25 (m, 4 H)7.33 (d, J=6.85 Hz, 2 H). Mass Spectrum (ESI) m/z=651.2 (M+1).

Example 1712-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)-N-(3,4-dihydroxybutyl)acetamide

To a solution ofN-(but-3-enyl)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetamide(0.030 g, 0.047 mmol; Example 170) in 1 mL of THF/H₂O (4:1) was addedosmium(VIII) oxide (0.030 mL, 2.363 μmol), followed by4-methylmorpholine-4-oxide (8.31 mg, 0.071 mmol). The reaction mixturewas stirred at room temperature for 12 h. Solvents were removed and theresidue was purified by reverse phase HPLC (40 to 90% water/acetonitrilegradient with 0.1% TFA). Desired fractions were then collected andconcentrated to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.51 (t, 3 H), 1.00 (t, J=7.24 Hz,2 H), 1.21 (d, J=4.11 Hz, 2 H), 1.42 (br. s., 3 H), 1.61 (br. s., 2 H),1.75-2.10 (m, 2 H) 2.26-2.44 (m, 2 H) 2.52-2.80 (m, 7 H) 2.88 (s, 3 H),3.21 (br. s., 2 H), 3.45-3.85 (m, 4 H), 4.23 (br. s., 1 H), 4.76 (d,J=10.56 Hz, 1 H), 6.90 (br. s., 1 H), 6.95-7.04 (m, 2 H), 7.07-7.15 (m,3 H) 7.23 (d, J=7.04 Hz, 2 H). Mass Spectrum (ESI) m/z=668 (M+1).

Example 1722-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared by a procedure similar to the onedescribed in Example 129, using the equivalent amount ofcyclopropanesulfonyl chloride instead of methanesulfonyl chloride inStep C. Purification of the residue by reverse phase preparatory HPLC(eluent: 10 to 90% acetonitrile, water, 0.1% TFA, gradient elution)provided the title compound as a white solid after lyophilization of thecollected fractions.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.54 (t, J=7.53 Hz, 3 H) 0.92-1.08(m, 2 H) 1.08-1.23 (m, 2 H) 1.39-1.64 (m, 4 H) 1.77-1.92 (m, 1 H)1.96-2.07 (m, 1 H) 2.28-2.49 (m, 2 H) 2.77 (d, J=14.28 Hz, 1 H) 2.92 (d,J=14.09 Hz, 1 H) 3.01-3.28 (m, 3 H) 3.61 (m, 1 H) 4.76 (d, J=10.56 Hz, 1H) 6.78-6.90 (m, 1 H) 6.90-7.18 (m, 5 H) 7.23 (m, 2 H).

Example 173(S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoicacid

Step A. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (0.055 g, 0.095 mmol; Example 141) in 1 mL of MeOH and 4 mL ofbenzene was added a 2.0 M solution of (trimethylsilyl)diazomethane indiethyl ether (0.095 mL, 0.189 mmol) at 0° C. The reaction mixture wasstirred at 0° C. for 0.5 h and was then concentrated. The crude materialwas purified by reverse phase preparatory HPLC (eluent: 10 to 90%acetonitrile, water, 0.1% TFA, gradient elution) to provide the titlecompound as a white powder after lyophilization of the pooled collectedfractions.

Step B. (S)-Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate

To a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate(0.040 g, 0.067 mmol) from Step A above and HMPA (0.012 mL, 0.067 mmol)in anhydrous THF (1 mL) was added LDA, 2.0M in THF (0.037 mL, 0.074mmol) at −78° C. Let it stir for 0.5 h at −78° C. Then iodomethane(0.057 mL, 0.913 mmol) was added. After stirring for 1 h, the reactionwas quenched with sat. aq. NH₄Cl solution and extracted with EtOAc. Theorganics were pooled, washed with sat. aq. NaCl solution, dried (MgSO₄),filtered and the filtrate was concentrated under the reduced pressure toprovide a yellow oil. This was used in the next step without furtherpurification.

Step C.S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoicacid

To a solution of (S)-methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoate(0.041 g, 0.067 mmol) from Step B above in MeOH/THF/H₂O (1 mL/1 mL/2 mL)was added lithium hydroxide (8.02 mg, 0.335 mmol). The mixture washeated to 60° C. for 14 h. The reaction mixture was acidified with 1NHCl and extracted with EtOAc (×2). The organics were pooled, washed withsat. aq. NaCl solution, dried (MgSO₄), filtered and the filtrate wasconcentrated under reduced pressure to provide a colorless film. Thecrude material was purified by reverse phase preparatory HPLC (eluent:10 to 90% acetonitrile, water, 0.1% TFA, gradient elution) to providethe title compound as the first eluting peak.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.52 (t, J=7.53 Hz, 3 H) 0.97-1.06(m, 2 H) 1.20-1.26 (m, 2 H) 1.41 (s, 3 H) 1.43-1.51 (m, 3 H) 1.57-1.70(m, 1 H) 1.88-2.04 (m, 2 H) 2.26-2.38 (m, 2 H) 2.78-2.97 (m, 5 H) 3.13(q, J=7.11 Hz, 1 H) 3.32 (ddd, J=13.55, 10.51, 3.13 Hz, 1 H) 4.86 (d,J=10.56 Hz, 1 H) 6.88-7.03 (m, 3 H) 7.10-7.16 (m, 2 H) 7.24 (m, 3 H).

Example 1742-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-(cyclopropanesulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Isomer 1)

Step A.N-((2S,3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentan-2-yl)cyclopropanesulfonamideandN-((2R,3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentan-2-yl)cyclopropanesulfonamide

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one(0.053 g, 0.115 mmol; mixture of stereoisomers; Example 149, Step A) andcyclopropanesulfonamide (0.042 g, 0.345 mmol) in toluene (2 mL) wasadded cyanomethylenetri-n-butylphosphorane (0.093 mL, 0.345 mmol) atroom temperature under an argon atmosphere, which solution was thenstirred at 110° C. for 2 days. Then the reaction was quenched (satNH₄Cl), extracted (3×EtOAc) and the combined extracts were washed (2×water and 1×sat. aq. NaCl solution). The combined organic layer wasdried (Na₂SO₄) and concentrated under reduced pressure. The crudematerial was purified by reversed phase preparatory HPLC (eluent: 10 to90% acetonitrile, water, 0.1% TFA, gradient elution) to provide thetitle compounds as two separate fractions.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(cyclopropanesulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared fromN—((S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentan-2-yl)cyclopropanesulfonamide(Example 174, Step A, faster eluting isomer) by a procedure similar tothe one described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.67 (t, J=7.43 Hz, 3 H) 0.92-1.04(m, 2 H) 1.04-1.19 (m, 2 H) 1.22 (d, J=6.85 Hz, 3 H) 1.50 (s, 3 H)1.79-1.93 (m, 1 H) 1.96-2.09 (m, 2 H) 2.28-2.42 (m, 2 H) 2.77 (d,J=13.89 Hz, 1 H) 2.92-2.96 (m, 2 H) 3.14-3.31 (m, 1 H) 4.54 (d, J=10.37Hz, 1 H) 6.80 (m, 1 H) 6.91-7.19 (m, 5 H) 7.21-7.27 (m, 2 H)

Example 1752-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-(cyclopropanesulfonamido)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Isomer 2)

The title compound was prepared fromN-((3S)-3-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)pentan-2-yl)cyclopropanesulfonamide(Example 174, Step A, slower eluting isomer) by a procedure similar tothe one described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.45-0.53 (m, 3 H) 0.97-1.12 (m, 2H) 1.18 (m, 1 H) 1.23-1.32 (m, 5 H) 1.52 (s, 3 H) 1.70 (m, 1H) 1.92 (m,2 H) 2.40-2.54 (m, 2 H) 2.74 (d, J=15.06 Hz, 1 H) 3.02 (d, J=15.06 Hz, 1H) 3.14 (m, 1 H) 4.85 (d, J=10.56 Hz, 1 H) 6.84 (m, 1 H) 6.99 (m, 1 H)7.08-7.17 (m, 2 H) 7.25 (m, 4 H)

Example 1762-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((3S)-2-(1-methylethylsulfonamido)pentan-3-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one(mixture of stereoisomers; Example 149, Step A) andpropane-2-sulfonamide by a procedure similar to the one described inExample 174.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.47 (t, J=7.83 Hz, 3 H) 1.20 (d,J=6.85 Hz, 3 H) 1.41 (dd, J=14.87, 6.85 Hz, 6 H) 1.51-1.60 (s, 3 H)1.60-1.73 (m, 1 H) 1.80-2.00 (m, 2 H) 2.50 (t, J=13.89 Hz, 1H) 2.72-2.81(d, J=14.67 Hz, 1 H) 2.97 (d, J=14.67 Hz, 1 H) 3.07-3.23 (m, 2 H) 4.85(d, J=10.96 Hz, 1 H) 6.87 (m, 1 H) 6.97-7.07 (m, 1 H) 7.07-7.19 (m, 2 H)7.19-7.33 (m, 4 H).

Example 1772-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoicacid

To a stirred solution of methyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoate(200 mg, 0.42 mmol; Example 91, Step A) in THF (5 mL) was added sodiumhydroxide (506 mg, 12.65 mmol) in water (5 mL) and the reaction washeated at reflux for about 12 h. After this time the reaction was cooledto rt and partitioned between EtOAc (80 mL) and 1.0 M HCl (20 mL). Theseparated aqueous layer was extracted with EtOAc (30 mL) and thecombined organic layers were dried over MgSO₄, filtered and the filtratewas evaporated in vacuo to give the title compound as a white solid.Mass Spectrum (ESI) m/z=460.0 (M+1).

Step B.(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)butanamide

To a stirred solution of2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoicacid (140 mg, 0.304 mmol; Example 177, Step A) in DMF (2 mL) was addedbromotripyrrolidin-1-ylphosphonium hexafluorophosphate (V) (354 mg, 0.76mmol) and N,N-diisopropylethylamine (0.11 mL, 0.61 mmol) and thereaction was stirred at rt for 3 hours. After this time the reaction waspartitioned between EtOAc (60 mL) and 1.0 M aq. LiCl solution (20 mL).The separated organic layer was dried over MgSO₄, filtered andevaporated in vacuo. Column chromatography (SiO₂, hexanes:EtOAc, 1:0 to1:1) gave the title compound. Mass Spectrum (ESI) m/z=563.0 (M+1).

Step C.(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)-N-methylbutanamide

To a stirred solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)butanamide(8 mg, 0.014 mmol; Example 177, Step B) in DMF (1.0 mL) was addedpotassium carbonate (2.9 mg, 0.021 mmol) and iodomethane (1.1 μL, 0.017mmol) at rt. The reaction was stirred for 1 hour. After this time moreiodomethane (1.1 μL, 0.017 mmol) and potassium carbonate (2.9 mg, 0.021mmol) was added and the reaction was stirred at rt for 60 hours. Afterthis time the reaction was partitioned between EtOAc (20 mL) and 1.0 MLiCl (5 mL). The separated organic layer was washed with 1.0 M LiCl (5mL), dried over MgSO₄, filtered and evaporated in vacuo to give thetitle compound.

Mass Spectrum (ESI) m/z=577.0 (M+1).

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(cyclopropylsulfonyl)-N-methylbutanamide(Example 177, Step C) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.30 (2 H, d, J=8.4 Hz), 7.15-7.25(4 H, m), 6.94 (2 H, d, J=7.6 Hz), 4.79-4.93 (2 H, m), 3.31 (3 H, s),3.08-3.17 (1 H, m), 2.92 (1 H, d, J=15.1 Hz), 2.70 (1 H, d, J=14.7 Hz),2.08-2.19 (2 H, m), 1.72 (2 H, t, J=7.5 Hz), 0.92-1.39 (8 H, m),0.84-0.91 (3 H, m). Mass Spectrum (ESI) m/z=595.0 (M+1).

Example 1782-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(neopentylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoicacid

To a stirred solution of2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanoicacid (110 mg, 0.24 mmol; Example 177, Step A or Example 1, Step F) andDIEA (0.050 ml, 0.287 mmol) in dry DMF (1195 μL) at 0° C. was added HATU(109 mg, 0.287 mmol). The reaction was stirred at 0° 5 min, followed byaddition of 2 eq. of neopentyl amine (55.9 μL, 0.478 mmol; TCI America).The reaction solution was stirred at 0° C. for 10 min until complete byLCMS, then filtered. Purification of the solution by reverse phasepreparatory HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford,Mass.), gradient elution of 70 to 100% MeCN in water over a 35 minperiod, where both solvents contain 0.1% TFA) provided the titlecompounds as an epimeric mixture.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(neopentylamino)-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained from2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-neopentylbutanamide(88 mg, 0.166 mmol) (Example 178, Step A) by a procedure similar to theone described in Example 71, Step F, followed by purification of theresidue by reverse phase HPLC (eluens: 55% MeCN/water (0.1% TFA),isocratic elution) using a Sunfire C18 OBD column, 10 uM, (30×150 mm),Waters Corp (Milford, Mass.).

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.79 (t, J=7.46 Hz, 3 H), 0.93 (s,9 H), 1.26 (s, 2 H), 1.43 (s, 3 H), 1.78 (dquin, J=14.38, 7.29, 7.29,7.29, 7.29 Hz, 1 H), 2.08-2.23 (m, 3 H), 2.81 (dd, J=13.20, 5.14 Hz, 1H), 2.88 (s, 2 H), 3.09 (dd, J=13.20, 6.60 Hz, 1 H), 3.17 (ddd, J=12.78,9.72, 3.67 Hz, 1 H), 3.92 (t, J=7.34 Hz, 1 H), 4.63 (d, J=9.78 Hz, 1 H),6.75 (d, J=7.58 Hz, 1 H), 6.94-7.00 (m, 3 H), 7.10 (t, J=7.70 Hz, 2 H),7.13-7.24 (m, 3 H). Mass Spectrum (ESI) m/z=547 (M+1).

Example 1792-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)butanamide

To a solution of2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)butanamide(Example 177, Step A) and 5 eq. of 2-amino-2-methylpropan-1-ol (80 μL,0.836 mmol; Sigma-Aldrich) in DMF (1672 μL) at 0° C. was added 1.2 eqHATU (76 mg, 0.201 mmol). The reaction solution was stirred for 1 hour,at which time the reaction was judged to be complete by LCMS. Thereaction mixture was diluted with EtOAc (50 mL) and washed with NaHCO₃(20 mL), 1N HCl, and water. The combined organic layers were dried overNa₂SO₄, filtered and the filtrate was concentrated to give the crudematerial as a clear solution (residual DMF present). The product wasused in the next step without further purification.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methylpiperidin-2-one

To a cold (−78° C.) solution of2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)butanamide(89 mg, 0.167 mmol; Example 179, Step A: epimeric mixture) in DCM (1674μL) was added 3 eq. of diethylaminosulfur trifluoride (26.5 μL, 0.201mmol) dropwise. The reaction mixture was stirred at −78° C. for 20 min.Anhydrous K₂CO₃ (1.5 equiv) was then added in one portion and themixture was allowed to warm to ambient temperature. The reaction waspoured into saturated aqueous NaHCO₃, and the biphasic mixture wasextracted with EtOAc×2. The combined organic extracts were dried overMgSO₄, filtered, and the filtrate was concentrated under reducedpressure. Purification of the residue by flash chromatography on silicagel (eluent: 0 to 20% ethyl acetate/hexane) provided the title compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.76 (t, J=7.46 Hz, 3 H), 1.08 (s,3 H), 1.15 (s, 3 H), 1.24 (s, 3 H), 1.67 (s, 1 H), 1.82 (dt, J=14.43,7.21 Hz, 1 H), 1.89-1.96 (m, 1 H), 2.00-2.11 (m, 1 H), 2.21 (dt,J=14.31, 7.27 Hz, 1 H), 2.61 (d, J=7.58 Hz, 2 H), 3.21 (ddd, J=13.14,10.09, 3.18 Hz, 1 H), 3.64 (d, J=7.83 Hz, 1 H), 3.90 (d, J=7.83 Hz, 1H), 4.12 (t, J=6.85 Hz, 1 H), 4.54 (d, J=10.27 Hz, 1 H), 5.16 (s, 1 H),5.18 (d, J=3.18 Hz, 1 H), 5.81-5.93 (m, 1 H), 6.75 (d, J=7.58 Hz, 1 H),7.00 (s, 3 H), 7.10 (t, J=7.70 Hz, 1 H), 7.15 (d, J=8.07 Hz, 1 H), 7.20(d, J=8.31 Hz, 2 H). Mass Spectrum (ESI) m/z=513 (M+1).

Further elution provided the other epimer:(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methylpiperidin-2-one.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.96 (t, J=7.46 Hz, 3 H), 1.19 (s,3 H), 1.27 (s, 3 H), 1.30 (s, 3 H), 1.65 (br. s., 1 H), 1.86-2.06 (m, 4H), 2.60 (qd, J=14.06, 7.70 Hz, 2 H), 3.20 (ddd, J=13.27, 10.09, 3.30Hz, 1 H), 3.79-3.89 (m, 2 H), 3.89-3.95 (m, 1 H), 4.49 (d, J=10.03 Hz, 1H), 5.15 (s, 1 H), 5.18 (d, J=3.91 Hz, 1 H), 5.82-5.95 (m, 1 H), 6.72(d, J=7.58 Hz, 1 H), 6.97 (t, J=1.83 Hz, 1 H), 7.08-7.13 (m, 1 H),7.13-7.23 (m, 3 H). Mass Spectrum (ESI) m/z=513 (M+1).

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)propyl)-3-methylpiperidin-2-one(53 mg, 0.103 mmol; Example 179, Step B) by a procedure similar to theone described in Example 71, Step F.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.74 (t, J=7.46 Hz, 3 H) 1.08 (s, 3H) 1.14 (s, 3 H) 1.41 (s, 3 H) 1.74 (dt, J=14.31, 7.03 Hz, 1 H)2.04-2.12 (m, 1 H) 2.12-2.30 (m, 2 H) 2.76 (d, J=14.43 Hz, 1 H) 2.88 (d,J=14.18 Hz, 1 H) 3.24 (ddd, J=12.59, 9.66, 3.18 Hz, 1 H) 3.66 (d, J=8.07Hz, 1 H) 3.88 (d, J=8.07 Hz, 1 H) 4.16 (t, J=6.72 Hz, 1 H) 4.60 (d,J=9.78 Hz, 1 H) 6.78 (d, J=7.58 Hz, 1 H) 6.99-7.06 (m, 2 H) 7.10 (t,J=7.82 Hz, 2 H) 7.14-7.18 (m, 1 H) 7.22 (d, J=8.31 Hz, 2 H). MassSpectrum (ESI) m/z=531 (M+1).

Example 1802-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(N-(2,2,2-trifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-(2,2,2-trifluoroethyl)acetamide

The title compound was obtained by acetylating(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((2,2,2-trifluoroethyl)amino)butan-2-yl)piperidin-2-one(Example 147, Step A) by a procedure similar to the one described inExample 28, Step C.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(N-(2,2,2-trifluoroethyl)acetamido)butan-2-yl)piperidin-3-yl)aceticacid

The title compound was obtained fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-(2,2,2-trifluoroethyl)acetamide(Example 180, Step A) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.52 (t, J=8.0 Hz, 3 H), 1.50 (s, 3H), 1.61 (m, 1 H), 1.87 (m, 1 H), 1.90-2.40 (m, 3 H), 2.27 (s, 3 H),2.77 (d, J=16.0 Hz, 1 H), 3.00 (d, J=16.0 Hz, 1 H), 3.10-3.30 (m, 2 H),3.43 (m, 1H), 3.85-4.05 (m, 3 H), 4.40 (d, J=8.0 Hz, 1 H), 6.71 (d,J=8.0 Hz, 1 H), 6.92 (s, 1 H), 7.01 (m, 2 H), 7.05-7.20 (m, 2 H), 7.25(d, J=8.0 Hz, 2 H).

Example 1812-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dimethylethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide

202.6 mg (0.454 mmol)(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 91, Step B) and 2-methylpropane-2-sulfonamide (130 mg, 0.948mmol, Oakwood) were dissolved in anhydrous toluene (4.5 mL).Cyanomethylenetributylphosphorane, 421 mg, was transferred to thereaction vessel via syringe. An additional ca. 30 mg of the phosphoranereagent was added 2 minutes after the first addition. The reactionmixture was stirred between 34-41° C. in a pre-heated oil bath. Thereaction was monitored by LCMS. An additional 133 mg of t-butylsulfonamide was added after 2 h 15 min the reaction mixture was heatedat 35° C. overnight.

On the following day, after 26 h, 15 min total reaction time, additional133 mg of t-butyl sulfonamide was added. 30 minutes later, an additional421 mg of cyanomethylenetributylphosphorane was added. Heating between35 to 40° C. was continued overnight.

On the third day, the reaction appeared complete by LCMS. After 53 htotal reaction time, the mixture was partitioned between ethyl acetateand saturated ammonium chloride. The aqueous phase was back extracted 2×with EtOAc, washed with sat. aq. NaCl solution, dried over sodiumsulfate, filtered, and the filtrate was concentrated in vacuo to aresidue that was chromatographed on a 24 g silica column, eluting with agradient of 0 to 30% EtOAc in hexanes. Fractions containing the desiredproduct by were combined and concentrated to give the title compound asan off-white solid that was dried under high vacuum. MS (ESI) m/z=565[M+H]⁺.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dimethylethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide(100 mg, 0.177 mmol; Example 181, Step A) was transferred to a roundbottom flask containing a stir bar, followed by carbon tetrachloride(1.100 mL), acetonitrile (1.1 mL), and water (1.6 mL). The flask wasthen charged with sodium periodate (190 mg, 0.888 mmol) andruthenium(III) chloride hydrate (6 mg, 0.023 mmol), and the resultingreddish-brown suspension was stirred vigorously at ambient temperature.After 18 h reaction time, an additional 200 mg of sodium periodate wereadded, along with another 2 mg of ruthenium(III) chloride hydrate.Stirring at ambient temperature was continued. After 4 h, the reactionwas quenched by addition of 1.3 M aq. HCl and diluted with ethylacetate. The resulting mixture was filtered. Sat. aq. NaCl solution wasadded to the aqueous phase to promote phase separation. Combinedorganics were washed with sat. aq. NaCl solution, dried over sodiumsulfate, filtered, and the filtrate was concentrated in vacuo. Theresulting residue was chromatographed on a Sunfire™ reverse-phase prepHPLC column (Waters, Milford, Mass.), eluting with a gradient of 50 to95% MeCN in water (0.1% TFA in both solvents) over the course of 35minutes. Fractions containing the desired product in high purity by HPLCwere combined, stripped of volatiles on the rotary evaporator, andlyophilized to provide the title compound as an off-white solid.

¹H NMR (500 MHz, CD₃OD) δ 0.46 (t, J=7.58 Hz, 3 H), 1.30-1.42 (m, 9 H),1.45 (s, 3 H), 1.52-1.66 (m, 1 H), 1.75-1.89 (m, 1 H), 1.96-2.10 (m, 1H), 2.33-2.49 (m, 1 H), 2.64 (d, J=13.45 Hz, 1 H), 2.72-2.83 (m, 1 H),2.88-2.97 (m, 1 H), 2.97-3.07 (m, 1 H), 3.32-3.40 (m, 1 H), 3.86-4.05(m, 1 H), 4.94-5.05 (m, 1 H), 6.79-7.45 (m, 8 H). MS (ESI) m/z=583[M+H]⁺.

Example 1822-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2-dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N,2-dimethylpropane-2-sulfonamide

N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-2-methylpropane-2-sulfonamide(100 mg, 0.177 mmol; Example 181, Step A) was dissolved in DMF (2.5 mL),and sodium hydride (60% dispersion in mineral oil, 19 mg, 0.45 mmol) wasadded in a single portion. After 25 minutes, this mixture was cooled to0° C. in an ice-water bath, and iodomethane (0.04 mL, 0.643 mmol) wasadded dropwise by syringe. The mixture was allowed to gradually warm toambient temperature, gradually becoming a pale yellow suspension. After2 h water (2 mL) was added very carefully. The resulting mixture waspartitioned between ethyl acetate and saturated aq. NH₄Cl solution. Theaqueous phase was back-extracted (2×) and the combined organics werewashed with sat. aq. NaCl solution (2×), dried over sodium sulfate,filtered, and the filtrate was concentrated in vacuo to an oily residuethat was chromatographed on a 12 g silica column, eluting with agradient of 0 to 35% EtOAc in hexanes. Fractions containing thesulfonamide product were pooled and concentrated to give the titlecompound. MS (ESI) m/z=579 [M+H]⁺.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,2-dimethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The compound was prepared fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N,2-dimethylpropane-2-sulfonamide(Example 182, Step A) by a procedure similar to the one described inExample 181, Step B. The crude material obtained was taken up inmethanol, filtered, and purified by reversed phase HPLC on a Sunfire™reverse phase prep HPLC column (Waters, Milford, Mass.), eluting with agradient of 50 to 100% MeCN in water (0.1% TFA in both solvents).Volatiles were removed and the suspension was re-dissolved with minimalMeCN, frozen, and lyophilized to give the title compound as an off-whitesolid.

¹H NMR (500 MHz, CD₃OD) δ 0.51 (t, J=7.21 Hz, 3 H), 1.32-1.48 (m, 12 H),1.58-1.71 (m, 1 H), 1.78-1.92 (m, 1 H), 1.94-2.06 (m, 1 H), 2.43 (t,J=13.69 Hz, 1 H), 2.63 (d, J=13.20 Hz, 1 H), 2.71-2.88 (m, 2 H),2.88-3.01 (m, 4 H), 3.28 (d, J=2.93 Hz, 0 H), 3.32-3.35 (m, 1 H), 4.40(br. s., 1 H), 4.79 (d, J=10.76 Hz, 1 H), 6.96-7.09 (m, 3 H), 7.10-7.40(m, 5 H). MS (ESI) m/z=597 [M+H]⁺.

Example 1832-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)propane-2-sulfonamide

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 91, Step B) and propane-2-sulfonamide as described in Example181, Step A. MS (ESI) m/z=551 [M+H]⁺.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)propane-2-sulfonamide(Example 183, Step A) by a procedure similar to the one described inExample 181, Step B. The residue was purified by reversed phase HPLC ona Sunfire™ reverse phase prep HPLC column (Waters, Milford, Mass.),eluting with a gradient of 50 to 100% MeCN in water (0.1% TFA in bothsolvents). Chromatography fractions were combined and concentrated invacuo.

The resulting suspension was made homogeneous by addition of minimalMeCN, frozen, and lyophilized to give the title compound.

¹H NMR (500 MHz, CD₃OD) δ 0.45 (t, J=7.58 Hz, 3 H), 1.35 (dd, J=8.56,6.85 Hz, 6 H), 1.41 (br. s., 3 H), 1.51-1.64 (m, 1 H), 1.83 (ddd,J=14.43, 8.56, 7.34 Hz, 1 H), 2.05 (dd, J=13.69, 2.93 Hz, 1 H), 2.39 (t,J=13.69 Hz, 1 H), 2.64 (d, J=13.45 Hz, 1 H), 2.80 (t, J=9.29 Hz, 1 H),2.87-3.04 (m, 2 H), 3.23 (dt, J=13.51, 6.82 Hz, 1 H), 3.33-3.40 (m, 1H), 3.85 (dd, J=14.06, 10.15 Hz, 1 H), 4.96 (d, J=11.00 Hz, 1 H),6.36-7.71 (m, 8 H). MS (ESI) m/z=569 [M+H]⁺.

Example 1842-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-ethylpropane-2-sulfonamide

The title compound was prepared fromN#S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)propane-2-sulfonamide(Example 183, Step A) by a procedure similar to the one described inExample 182, Step A, replacing iodomethane with iodoethane. MS (ESI)m/z=579 [M+H]⁺.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylpropan-2-ylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-ethylpropane-2-sulfonamide(Example 184, Step A) by a procedure similar to the one described inExample 71, Step F. The residue was chromatographed on a Sunfire™ C18reverse phase prep HPLC column (Waters, Milford, Mass.), eluting with agradient of 50 to 100% MeCN in water (0.1% TFA in both solvents).Fractions containing the product in high purity by HPLC were combinedand stripped of volatiles on the rotary evaporator. The suspension wasre-dissolved in minimal MeCN, frozen, and lyophilized overnight to givethe title compound as a white foam.

¹H NMR (500 MHz, CD₃OD) δ 0.52 (t, J=7.21 Hz, 3 H), 1.09-1.20 (m, 3 H),1.30 (d, J=6.85 Hz, 3 H), 1.38 (d, J=6.85 Hz, 3 H), 1.43 (s, 3 H),1.56-1.69 (m, 1 H), 1.82-1.97 (m, 1 H), 2.01 (dd, J=13.69, 2.93 Hz, 1H), 2.41 (t, J=13.69 Hz, 1 H), 2.64 (d, J=13.20 Hz, 1 H), 2.82 (br. s.,1 H), 2.88-3.02 (m, 2 H), 3.15-3.25 (m, 1 H), 3.28 (d, J=3.18 Hz, 1 H),3.33-3.36 (m, 1 H), 3.40-3.55 (m, 1 H), 4.29 (d, J=6.36 Hz, 1 H), 4.84(br. d, J=1.00 Hz, 1 H), 6.81-7.55 (m, 8 H). MS (ESI) m/z=597 [M+H]⁺.

Example 1852-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. (S)-Methyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate

To a 50° C. solution of 33.8 g (60% in mineral oil, 845 mmol) of sodiumhydride in 2-methyltetrahydrofuran (550 mL) was added a solution of 240g (750 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1,Step E) in 2-methyltetrahydrofuran (550 mL) over a period of 45 min.After an additional 1.25 h at 50° C., 105 mL (912 mmol) of methyl2-bromobutyrate was added over a 20 min period. The resulting slurry wasstirred at 50° C. for 3.5 h, and then was cooled to room temperature andquenched with saturated aq. NH₄Cl solution. Water was added to dissolvethe precipitate and the resulting mixture was extracted with ethylacetate (4×). The combined organic layers were washed with sat. aq. NaClsolution (1×), dried over Na₂SO₄, filtered and the filtrate wasconcentrated. Purification of the residue by chromatography on silicagel (Biotage® Snap™ column (Biotage, LLC, Charlotte, N.C.), 0 to 35%EtOAc/DCM, gradient elution) provided the title compound as a white oilysolid.

Step B.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

To an ice-cooled solution of 48.5 g (115 mmol) of (S)-methyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butanoate(Example 185, Step A) in ethyl ether (850 mL) was added 5.96 g (90%, 246mmol) of lithium borohydride. The resulting light yellow solution wasstirred at 0° C. for 3 h, and then MeOH (2.5 mL) and more ethyl ether(100 mL) were added. Gas evolution was observed upon the addition ofMeOH. After 40 min, the reaction was quenched by cautious addition of 1N HCl until bubbling subsided. The mixture was extracted with EtOAc(2×), and the combined organic layers were washed with saturated aqueoussodium chloride (1×). The organic layer was dried over Na₂SO₄, filteredand the filtrate was concentrated to afford the title compound as awhite foam. The crude product was used directly in the next step withoutfurther purification.

Step C.(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one

To a solution of 44.7 g (114 mmol) of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-14S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 185, Step B) and 19.4 g (285 mmol) of imidazole in DMF (350 mL)was added 39.4 mL (154 mmol) of tert-butyldiphenylsilyl chloride. Thecolorless solution was stirred at room temperature for 17 h. Thereaction was partitioned between water and ethyl ether (3×), and thenthe combined organic layers were washed with saturated aqueous sodiumchloride (1×), dried over Na₂SO₄, filtered and the filtrate wasconcentrated. Purification of the residue by chromatography on silicagel (Biotage® Snap™ column (Biotage, LLC, Charlotte, N.C.), 0 to 60%EtOAc/hexanes, gradient elution) provided the title compound as a whitefoam.

Step D.(5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

To a −78° C. solution of 98.2 g (156 mmol) of(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 185, Step C) and 10.0 mL (160 mmol) of methyl iodide in dry,degassed THF (400 mL) was added 200 mL (200 mmol) of a degassed 1 Msolution of lithium bis(trimethylsilyl)amide in THF slowly over 20 min.The orange solution was stirred at −78° C. for 1.5 h and then warmed to0° C. and stirred for an additional 1.5 h. The reaction was quenchedwith saturated aqueous ammonium chloride, and extracted with EtOAc (3×).The combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. Purification of the residue by chromatographyon silica gel (Biotage® Snap™ column; Biotage, LLC, Charlotte, N.C.),5-55% EtOAc/hexanes, gradient elution) provided the title compound as alight yellow foam.

Step E.(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

To a −78° C. solution of 37.3 mL (266 mmol) of diisopropylamine in dry,degassed THF (150 mL) was added 100 mL (250 mmol) of a degassed 2.5 Msolution of n-butyllithium in hexanes slowly via cannula. The lightyellow solution was stirred at −78° C. for 15 min, then was warmed to 0°C. and stirred for an additional 5 min. To the ice-cooled LDA solutionwas added a solution of 85.7 g (133 mmol) of(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 185, Step D) in dry, degassed THF (210 mL) via cannula over a15 min period. The dark orange solution was stirred at 0° C. for 30 minand then 34.5 mL (399 mmol) of allyl bromide was added quickly viasyringe. After 20 sec, the ice bath was removed and the reaction wasplaced in a room temperature water bath and stirred for an additional 15min. The reaction was quenched with saturated aq. ammonium chloride, andextracted with EtOAc (3×). The combined organic layers were dried overNa₂SO₄, filtered and the filtrate was concentrated. Purification of theresidue by chromatography on silica gel (Biotage® Snap™ column; Biotage,LLC, Charlotte, N.C.), 6-14% EtOAc/hexanes, gradient elution) providedthe title compound as a white foam.

Step F.2-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 185, Step E) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.30 (t, J=7.53 Hz, 3 H) 1.17 (s, 9H) 1.34-1.48 (m, 1 H) 1.53 (s, 3 H) 1.74-1.88 (m, 1 H) 1.93-2.03 (m, 1H) 2.29 (t, J=13.69 Hz, 1 H) 2.69 (d, J=15.85 Hz, 1 H) 2.81-2.93 (m, 1H) 2.98-3.08 (m, 1 H) 3.12 (d, J=15.65 Hz, 1 H) 3.52 (dd, J=10.66, 4.21Hz, 1 H) 4.32 (t, J=10.27 Hz, 1 H) 4.71 (d, J=10.76 Hz, 1H) 6.56-6.66(m, 1 H) 6.91-6.97 (m, 1 H) 7.02-7.09 (m, 1 H) 7.12-7.18 (m, 1 H)7.20-7.30 (m, 4 H) 7.33-7.51 (m, 6 H) 7.64 (td, J=7.83, 1.57 Hz, 4 H).

Step G.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To an ice-cooled solution of 370 g (0.53 mmol) of2-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 185, Step F) in THF (15 mL) was added 2.60 mL (2.60 mmol)of a 1 M solution of TBAF in THF. The yellow solution was warmed to rtand stirred for 5 h. At this time 2.60 mL (2.60 mmol) of a 1 M solutionof TBAF in THF was added and the reaction was stirred for an additional20 h. The reaction was partitioned between 1 N HCl and EtOAc (4×). Thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated. The residue was purified by reverse phaseprep. HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column (Waters, Milford, Mass.),gradient elution of 40% MeCN in water to 80% MeCN in water over a 30 minperiod, where both solvents contain 0.1% TFA) provided the titlecompound as a white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.23-7.28 (2 H, m), 7.15-7.20 (1 H, m),7.07-7.14 (1 H, m), 6.98-7.06 (3 H, m), 6.74 (1 H, d, J=7.1 Hz), 4.55 (1H, dd J=9.8 Hz, 2.9 Hz), 3.71-3.79 (1 H, m), 3.58-3.66 (1 H, m),3.19-3.28 (1 H, m), 3.07-3.16 (1 H, m), 2.96-3.03 (1 H, m), 2.75 (1 H,dd, J=14.9 Hz, 2.9 Hz), 2.16-2.25 (1 H, m), 2.03-2.10 (1 H, m),1.87-1.98 (1 H, m), 1.46 (3 H, s), 1.41-1.54 (m, 1 H), 0.63 (3 H, dd,J=7.3 Hz, 3.3 Hz). Mass Spectrum (ESI) m/z=464.1 (M+1).

Example 1862-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)aceticacid

Step A. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate

A solution of2-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 185) in MeOH (2 mL) and benzene (8 mL) was stirred with(trimethylsilyl)diazomethane, 2.0 M in diethyl ether (2.02 mL, 4.04mmol) at rt for 0.5 h. After that time the mixture was concentrated togive the crude methyl ester, which was treated with TBAF in THF at rtfor 30 h. The mixture was concentrated and purified by chromatography onsilica gel (0 to 100% EtOAc in hexanes) to give the title compound. MassSpectrum (ESI) m/z=478 (M+1).

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)aceticacid

A reaction vial under argon was charged with methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(0.048 g, 0.1 mmol; Example 186, Step A),2-(tributylphosphoranylidene)acetonitrile (0.036 g, 0.15 mmol) andtrifluoromethanesulfonamide (0.022 g, 0.15 mmol) in toluene (0.5 mL).The reaction mixture in the reaction vial was sealed and stirred at 110°C. for 1 h. Column chromatography on silica gel gave a mixture of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(trifluoromethylsulfonamido)butan-2-yl)piperidin-3-yl)acetatewith an unknown impurity. This mixture was hydrolyzed with LiOH (1Nsolution in water, 0.3 mL) in ethanol (0.5 mL) for 3 h at rt. HPLCpurification (C18 column, eluted with 10 to 95% CH₃CN in water, with0.1% TFA) gave the title compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.26 (2 H, br. s.), 7.15-7.20 (1 H,m), 7.12 (1 H, t, J=7.8 Hz), 7.05 (1 H, d, J=9.3 Hz), 6.95 (1 H, t,J=1.7 Hz), 6.75 (1 H, d, J=7.6 Hz), 6.49 (1 H, br. s.), 4.53 (1 H, d,J=10.3 Hz), 3.13-3.27 (3 H, m), 2.80-2.93 (3 H, m), 2.24 (1 H, t, J=13.8Hz), 2.10 (1 H, dd, J=14.1, 3.1 Hz), 1.83 (1 H, br. s.), 1.55-1.66 (1 H,m), 1.49 (3 H, s), 0.71 (3 H, br. s.). Mass Spectrum (ESI) m/z=595(M+1).

EXAMPLES 187-195 were, unless noted otherwise, prepared from methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 186, Step A) by procedures similar to the one described inExample 186, Step B, replacing trifluoromethanesulfonamide with theappropriate reagent.

Example R Reagent used 187

4- Chlorobenzenesulfonamide 188

4- Methylbenzenesulfonamide 189

2- Chlorobenzenesulfonamide 190

2- Methylbenzenesulfonamide 191

4- Methoxybenzenesulfonamide 192

Benzenesulfonamine 193

1-Methylcyclopropane-1- sulfonamide 194

2,3-Dihydro-1,1-dioxo-1,2- benzisothiazole 195

2,3-Dihydro-3,3-dimethyl- 1,2- benzisothiazole 1,1-dioxide

Example 1872-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-chlorophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.77 (2 H, m, J=8.6 Hz), 7.48-7.54(2 H, m), 7.23 (2 H, d, J=8.1 Hz), 7.11-7.19 (2 H, m), 7.05 (2 H, d,J=5.9 Hz), 6.98 (1 H, s), 6.86 (1 H, d, J=7.3 Hz), 5.31 (2 H, br. s.),5.26 (3 H, br. s.), 4.78 (1 H, d, J=10.3 Hz), 3.43 (1 H, br. s.), 3.17(2 H, ddd, J=13.5, 10.7, 2.9 Hz), 2.97 (1 H, d, J=14.4 Hz), 2.79 (1 H,d, J=14.4 Hz), 2.74 (1 H, d, J=13.7 Hz), 2.38 (1 H, t, J=13.8 Hz), 2.05(1 H, dd, J=13.9, 2.9 Hz), 1.80 (1 H, dt, J=14.6, 7.5 Hz), 1.52 (3 H,s), 1.43-1.50 (1 H, m), 0.51 (3 H, t, J=7.1 Hz). Mass Spectrum (ESI)m/z=637 (M+1).

Example 1882-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(4-methylphenylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.72 (2 H, m, J=8.3 Hz), 7.33 (2 H,m, J=8.1 Hz), 7.23 (2 H, d, J=8.1 Hz), 7.11-7.19 (2 H, m), 7.05 (2 H, d,J=6.6 Hz), 6.96-6.99 (1 H, m), 6.85-6.91 (1 H, m), 4.95 (1 H, br. s.),4.83 (1 H, d, J=10.5 Hz), 3.49 (1 H, br. s.), 3.14 (2 H, ddd, J=13.4,10.6, 2.8 Hz), 3.02 (1 H, d, J=14.9 Hz), 2.70-2.81 (2 H, m), 2.45 (3 H,s), 2.36-2.44 (1 H, m), 2.01 (1 H, dd, J=13.9, 2.9 Hz), 1.81 (1 H, dd,J=15.3, 7.5 Hz), 1.53 (3 H, s), 1.47 (1 H, ddd, J=14.2, 7.6, 4.3 Hz),0.47 (3 H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=617 (M+1).

Example 1892-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-chlorophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.77 (2 H, m, J=8.6 Hz), 7.48-7.54(2 H, m), 7.23 (2 H, d, J=8.1 Hz), 7.11-7.19 (2 H, m), 7.05 (2 H, d,J=5.9 Hz), 6.98 (1 H, s), 6.86 (1 H, d, J=7.3 Hz), 5.31 (2 H, br. s.),5.26 (3 H, br. s.), 4.78 (1 H, d, J=10.3 Hz), 3.43 (1 H, br. s.), 3.17(2 H, ddd, J=13.5, 10.7, 2.9 Hz), 2.97 (1 H, d, J=14.4 Hz), 2.79 (1 H,d, J=14.4 Hz), 2.74 (1 H, d, J=13.7 Hz), 2.38 (1 H, t, J=13.8 Hz), 2.05(1 H, dd, J=13.9, 2.9 Hz), 1.80 (1 H, dt, J=14.6, 7.5 Hz), 1.52 (3 H,s), 1.43-1.50 (1 H, m), 0.51 (3 H, t, J=7.1 Hz). Mass Spectrum (ESI)m/z=651 (M+1).

Example 1902-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(2-methylphenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.89 (1 H, d, J=7.8 Hz), 7.46-7.52(1 H, m), 7.31-7.38 (2 H, m), 7.23 (2 H, d, J=7.8 Hz), 7.12-7.18 (2 H,m), 7.06 (2 H, br. s.), 6.99 (1 H, s), 6.88 (1 H, d, J=7.1 Hz), 5.16 (1H, br. s.), 4.85 (1 H, d, J=10.5 Hz), 4.46 (3 H, br. s.), 3.44 (1 H, br.s.), 3.11-3.22 (2 H, m), 2.99 (1 H, d, J=14.9 Hz), 2.73-2.84 (2 H, m),2.67 (3 H, s), 2.36-2.47 (1 H, m), 2.04 (1 H, dd, J=13.9, 2.9 Hz), 1.80(1 H, dt, J=14.7, 7.7 Hz), 1.53 (3 H, s), 1.45 (1 H, ddd, J=14.1, 7.6,4.4 Hz), 0.46 (3 H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=617 (M+1).

Example 1912-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-methoxyphenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.76 (2 H, d, J=8.8 Hz), 7.24 (2 H,d, J=7.8 Hz), 7.11-7.19 (2 H, m), 7.04 (1 H, br. s.), 7.01 (1 H, s),6.98 (2 H, d, J=4.4 Hz), 6.88 (1 H, d, J=6.8 Hz), 4.92 (1 H, br. s.),4.83 (1 H, d, J=10.5 Hz), 4.03 (3 H, br. s.), 3.89 (3 H, s), 3.49 (1 H,br. s.), 3.14 (2 H, t, J=10.8 Hz), 3.02 (1 H, d, J=14.9 Hz), 2.69-2.80(2 H, m), 2.42 (1 H, t, J=13.8 Hz), 1.97-2.05 (1 H, m), 1.82 (1 H, dt,J=14.6, 7.5 Hz), 1.53 (3 H, s), 1.41-1.50 (1 H, m), 0.47 (3 H, t, J=7.3Hz). Mass Spectrum (ESI) m/z=633 (M+1).

Example 1922-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(phenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.84 (2 H, d, J=7.3 Hz), 7.62 (1 H,t, J=7.3 Hz), 7.55 (2 H, t, J=7.7 Hz), 7.24 (2 H, d, J=8.1 Hz),7.12-7.19 (2 H, m), 7.05 (2 H, d, J=6.6 Hz), 6.98 (1 H, s), 6.87 (1 H,d, J=6.8 Hz), 5.03 (1 H, br. s.), 4.82 (1 H, d, J=10.5 Hz), 4.01 (2 H,br. s.), 3.49 (1 H, br. s.), 3.09-3.21 (2 H, m), 3.02 (1 H, d, J=14.9Hz), 2.77 (2 H, d, J=14.7 Hz), 2.41 (1 H, t, J=13.8 Hz), 2.02 (1 H, dd,J=13.9, 2.7 Hz), 1.82 (1 H, dt, J=14.9, 7.6 Hz), 1.53 (3 H, s), 1.48 (1H, ddd, J=14.2, 7.7, 4.5 Hz), 0.49 (3 H, t, J=7.5 Hz). Mass Spectrum(ESI) m/z=603 (M+1).

Example 1932-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1-methylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24 (2 H, d, J=7.8 Hz), 7.10-7.17(2 H, m), 7.03 (1 H, s), 7.06 (1 H, s), 6.95-6.97 (1 H, m), 6.84-6.89 (1H, m), 4.88 (2 H, br. s.), 4.81 (2 H, d, J=10.5 Hz), 4.71 (1 H, br. s.),3.71 (1 H, br. s.), 3.03-3.18 (3 H, m), 2.96-3.02 (1 H, m), 2.76 (1 H,d, J=14.7 Hz), 2.40 (1 H, t, J=13.8 Hz), 1.98 (1 H, dd, J=13.9, 2.9 Hz),1.88 (1 H, dt, J=15.0, 7.5 Hz), 1.52 (3 H, s), 1.50 (3H, s), 1.45-1.49(1 H, m), 1.33-1.43 (2 H, m), 0.77-0.86 (2 H, m), 0.52 (3 H, t, J=7.5Hz). Mass Spectrum (ESI) m/z=581 (M+1).

Example 1942-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.91 (1 H, d, J=7.6 Hz), 7.66-7.72(1 H, m), 7.60-7.65 (1 H, m), 7.43 (1 H, d, J=7.6 Hz), 7.25 (1 H, br.s.), 7.06-7.11 (1 H, m), 6.95-7.06 (3 H, m), 6.87 (1 H, s), 6.71 (1 H,d, J=7.6 Hz), 4.86 (1 H, d, J=10.3 Hz), 4.36-4.47 (2 H, m), 4.20 (1 H,dd, J=14.2, 10.5 Hz), 4.03 (5 H, br. s.), 3.24 (1 H, dd, J=14.7, 3.4Hz), 3.01-3.15 (3 H, m), 2.74 (1 H, d, J=14.9 Hz), 2.32 (1 H, t, J=13.8Hz), 1.95-2.07 (1 H, m), 1.90 (1 H, dd, J=13.8, 2.8 Hz), 1.53 (1 H, ddd,J=10.7, 7.4, 3.9 Hz), 1.49 (3 H, s), 0.53 (3 H, t, J=7.5 Hz). MassSpectrum (ESI) m/z=615 (M+1).

Example 1952-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-dimethyl-1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.88 (1 H, d, J=7.6 Hz), 7.68-7.74(1 H, m), 7.58-7.64 (1 H, m), 7.45 (1 H, d, J=7.8 Hz), 7.25 (1 H, br.s.), 7.02-7.12 (3 H, m), 6.99 (1 H, t, J=7.8 Hz), 6.94 (1 H, s), 6.75 (1H, d, J=7.6 Hz), 5.02 (1 H, d, J=10.0 Hz), 4.24 (1 H, dd, J=14.8, 10.6Hz), 3.15 (2 H, d, J=13.0 Hz), 3.03-3.13 (3 H, m), 2.92 (8 H, br. s.),2.71 (1 H, d, J=15.4 Hz), 2.36 (1 H, t, J=13.6 Hz), 2.06-2.19 (1 H, m),1.90 (1 H, dd, J=13.8, 3.1 Hz), 1.57 (3 H, s), 1.48-1.52 (4 H, m), 1.47(3 H, s), 0.51 (3 H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=643 (M+1).

Example 1962-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)aceticacid, as the 2,2,2-trifluoroacetic acid salt

Step A. Methyl2-((3R,5R,6S)-1-((S)-1-(bis(tert-butoxycarbonyl)amino)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate

A solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(282 mg, 0.589 mmol; Example 186, Step A),2-(tributylphosphoranylidene)acetonitrile (171 mg, 0.707 mmol) anddi-tert-butyl iminodicarbonate (256 mg, 1.179 mmol) in toluene (3 mL)under argon was stirred at 110° C. for 2 h. Flash column purification onsilica gel (0 to 60% EtOAc in hexanes) gave the title compound. MassSpectrum (ESI) m/z=677 (M+1).

Step B. Methyl2-((3R,5R,6S)-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate

A solution of methyl2-((3R,5R,6S)-1-((S)-1-(bis(tert-butoxycarbonyl)amino)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(167 mg, 0.246 mmol) prepared in Step A above in dioxane was stirredwith HCl (4M, 0.6 mL) at rt for 2 h. Chromatography on silica gel (0 to20% MeOH/DCM) gave the title compound. Mass Spectrum (ESI) m/z=477(M+1).

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)aceticacid

A solution of methyl2-((3R,5R,6S)-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(13 mg, 0.027 mmol; Example 196, Step A) and pyridine-3-sulfonylchloride (4.84 mg, 0.027 mmol) in pyridine (0.3 mL) was stirred at 110°C. for 4 h. Chromatography on silica gel (0 to 60% EtOAc in hexanes)gave methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridine-3-sulfonamido)butan-2-yl)piperidin-3-yl)acetate.This was hydrolyzed with LiOH (1N solution in water, 0.3 mL) in ethanol(0.5 mL) for 3 h at rt. HPLC purification (C18 column, eluted with 10 to95% CH₃CN in water, with 0.1% TFA) gave the title compound as a 1:1complex with 2,2,2-trifluoroacetic acid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 9.29 (1 H, br. s.), 8.90 (1 H, d,J=4.4 Hz), 8.32 (1 H, d, J=8.1 Hz), 7.66-7.76 (1 H, m), 7.15 (1 H, d,J=8.1 Hz), 7.10 (1 H, t, J=7.8 Hz), 7.02 (2 H, s), 7.06 (1 H, s), 6.94(1 H, s), 6.74 (1 H, d, J=7.3 Hz), 4.60 (1 H, d, J=9.0 Hz), 3.18 (1 H,ddd, J=13.4, 10.4, 2.8 Hz), 2.86 (4 H, br. s.), 2.27-2.35 (3 H, m), 2.03(2 H, dd, J=14.1, 3.1 Hz), 1.66 (1 H, br. s.), 1.54-1.64 (1 H, m), 1.48(3 H, s), 0.72 (3 H, br. s.). Mass Spectrum (ESI) m/z=604 (M+1).

EXAMPLES 197-199 were also prepared from methyl2-((3R,5R,6S)-1-((S)-1-aminobutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 196, Step B) by procedures similar to the one described inExample 196, Step C, replacing pyridine-3-sulfonyl chloride with theappropriate reagent.

Example R Reagent used 197

4-Cyanobenzene-1-sulfonyl chloride 198

3-Cyanobenzene-1-sulfonyl chloride 199

Pyridine-2-sulfonyl chloride

Example 1972-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(4-cyanophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.95 (2 H, m, J=8.6 Hz), 7.81-7.87(2 H, m), 7.22 (2 H, d, J=8.1 Hz), 7.16-7.20 (1 H, m), 7.11-7.16 (1 H,m), 7.06 (1 H, s), 6.98 (1 H, t, J=1.7 Hz), 6.80 (1H, d, J=7.6 Hz), 5.41(1H, br. s.), 4.68 (1 H, d, J=10.0 Hz), 3.38 (1H, br. s.), 3.17 (1H,ddd, J=13.5, 10.5, 2.7 Hz), 2.98 (1 H, d, J=14.7 Hz), 2.78 (1 H, d,J=14.7 Hz), 2.69-2.76 (1 H, m), 2.35 (1 H, t, J=13.8 Hz), 2.00-2.08 (2H, m), 1.55 (1 H, d, J=7.6 Hz), 1.52 (4 H, s), 0.59 (3 H, br. s.). MassSpectrum (ESI) m/z=628 (M+1).

Example 1982-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-cyanophenylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.15 (1 H, t, J=1.5 Hz), 8.07 (1 H,d, J=7.8 Hz), 7.89 (1 H, dt, J=7.8, 1.2 Hz), 7.70 (1 H, t, J=7.9 Hz),7.20 (2 H, d, J=7.8 Hz), 7.17 (1 H, dt, J=8.3, 1.5 Hz), 7.13 (1 H, t,J=7.7 Hz), 7.06 (1 H, s), 6.97 (1 H, s), 6.80 (1 H, d, J=7.3 Hz), 5.49(1 H, br. s.), 4.68 (1 H, d, J=10.0 Hz), 3.40 (1 H, br. s.), 3.27 (1 H,br. s.), 3.17 (1 H, ddd, J=13.4, 10.5, 2.9 Hz), 2.97 (1 H, d, J=14.9Hz), 2.80 (1 H, d, J=14.7 Hz), 2.76 (1 H, br. s.), 2.35 (1 H, t, J=13.7Hz), 2.04 (1 H, dd, J=13.9, 2.9 Hz), 1.56 (1 H, d, J=7.1 Hz), 1.52 (3 H,s), 0.61 (3 H, br. s.). Mass Spectrum (ESI) m/z=628 (M+1).

Example 1992-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridine-2-sulfonamido)butan-2-yl)piperidin-3-yl)aceticacid. Compound obtained as 2,2,2-trifluoroacetic acid salt

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.73 (1 H, d, J=4.2 Hz), 7.93-8.04(2 H, m), 7.53-7.60 (1 H, m), 7.18-7.24 (2 H, m), 7.11-7.18 (2 H, m),7.00-7.09 (2 H, m), 6.98 (1 H, s), 6.87 (1 H, d, J=6.8 Hz), 5.54 (1 H,br. s.), 4.82 (1 H, d, J=10.5 Hz), 3.51 (1 H, br. s.), 3.22 (1 H, br.s.), 3.10-3.18 (1 H, m), 3.03 (1 H, d, J=14.9 Hz), 2.94 (1 H, dt,J=14.0, 4.1 Hz), 2.75 (1 H, d, J=14.9 Hz), 2.44 (1 H, t, J=13.7 Hz),1.99 (4 H, dd, J=14.1, 2.8 Hz), 1.78-1.83 (3 H, m), 1.54 (3 H, s),1.43-1.53 (2 H, m), 0.51 (3 H, t, J=7.3 Hz). Mass Spectrum (ESI) m/z=604(M+1).

Example 2002-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

A solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(1-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)acetate(21.7 mg, 0.036 mmol; Example 193),2-(tributylphosphoranylidene)acetonitrile (8.8 mg, 0.036 mmol) and onedrop of MeOH in toluene (0.5 mL) was stirred at 110° C. for 1 h. Flashcolumn purification on silica gel (0 to 60% EtOAc in hexanes) gavemethyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N,1-dimethylcyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate.This was hydrolyzed with LiOH (1N solution in water, 0.3 mL) in ethanol(0.5 mL) for 3 h at rt. HPLC purification (C18 column, eluted with 10 to95% CH₃CN in water, with 0.1% TFA) gave the title compound.

¹H ¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.26 (2 H, br. s.), 7.13 (2 H,d, J=3.7 Hz), 6.94 (2 H, br. s.), 6.88 (1 H, br. s.), 4.80 (1 H, d,J=9.5 Hz), 4.36 (1 H, br. s.), 2.96-3.12 (3 H, m), 2.86-2.93 (4 H, m),2.79 (3 H, d, J=14.2 Hz), 2.69 (3 H, d, J=15.4 Hz), 2.41-2.64 (15 H, m),1.96 (1 H, dd, J=14.4, 7.3 Hz), 1.84 (1 H, d, J=13.7 Hz), 1.55-1.64 (2H, m), 1.53 (3 H, br. s.), 1.38-1.48 (6 H, m), 0.81 (2 H, br. s.), 0.51(3 H, t, J=6.2 Hz). Mass Spectrum (ESI) m/z=595 (M+1).

Example 2013-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoicacid or3-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoicacid

Step A.(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

To a mixture of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(20.00 g, 51.0 mmol; Example 185, Step B) andN-methylcyclopropanesulfonamide (10.34 g, 76 mmol) in 100 mL of tolueneat room temperature was added cyanomethylenetributylphosphorane (20.51mL, 76 mmol). The resulting mixture was heated to 130° C. for 12 h, thencooled to room temperature and directly loaded onto a silica gel columnfor purification, eluting with 0 to 10% MeOH in DCM to provide the titlecompound. Mass Spectrum (ESI) m/z=509 (M+1).

Step B.N-((2S)-2-((2S,3R)-3-(3-Chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

The title compound was obtained as a mixture of diastereomers fromN—((S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 201, Step A) using a procedure similar to one described inExample 185, Step D. Mass Spectrum (ESI) m/z=523 (M+1).

Step C.N—((S)-2-((5R,6S)-3-(But-3-enyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Isomer 1)

To a solution ofN-((2S)-2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-5-methyl-6-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(2618 mg, 5.0 mmol; Example 201, Step B) in degassed THF (10 mL) wasadded lithium diisopropylamide (5.00 mL, 10.00 mmol) at −15° C. Afterstirring at −15° C. for 30 min, the reaction mixture was cooled to −74°C. 4-Bromobut-1-ene (1.066 mL, 10.50 mmol) was added slowly. Thereaction mixture was stirred at −74° C. for 3 h before warming up to rtand then stirred at rt for 66 h. Filtered and purified by HPLC (C18column, eluted with 10 to 95% CH₃CN in water, with 0.1% TFA) to give thetitle compound as the first eluting isomer Its stereoisomer is obtainedas the later eluting isomer.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.22 (2 H, d, J=7.6 Hz), 7.10-7.17(2 H, m), 6.96 (2 H, s), 6.90-6.95 (1 H, m), 5.90 (1 H, ddt, J=17.0,10.3, 6.4, 6.4 Hz), 5.10 (1 H, dd, J=17.1, 1.5 Hz), 5.03 (1 H, dd,J=10.0, 1.5 Hz), 4.77 (1 H, d, J=10.5 Hz), 4.24 (1 H, br. s.), 3.07 (1H, ddd, J=13.7, 10.6, 3.1 Hz), 2.90 (3 H, s), 2.74-2.87 (2 H, m),2.24-2.37 (2 H, m), 2.11-2.21 (2 H, m), 2.00 (1 H, ddd, J=13.6, 10.1,6.6 Hz), 1.78-1.93 (3 H, m), 1.60-1.70 (1 H, m), 1.58 (2 H, br. s.),1.28-1.32 (3 H, m), 1.22 (2 H, d, J=3.2 Hz), 0.95-1.04 (2 H, m), 0.53 (3H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=577 (M+1).

Step D.3-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoicacid or3-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)propanoicacid

The title compound was obtained fromN—((S)-2-((5R,6S)-3-(but-3-enyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Isomer 1, 604 mg, 1.046 mmol; Example 201, Step C) by a proceduresimilar to the one described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23 (2 H, d, J=7.4 Hz), 7.11-7.17(3 H, m), 6.98 (2 H, m), 6.89-6.94 (1 H, m), 4.75 (1H, d, J=11.3 Hz),4.24 (1 H, br. s.), 3.17 (1 H, ddd, J=13.8, 10.8, 3.1 Hz), 2.89 (3 H,s), 2.63-2.82 (3 H, m), 2.55 (1 H, dd, J=8.5, 6.2 Hz), 2.39-2.52 (2 H,m), 2.27-2.39 (2 H, m), 1.82-1.94 (2 H, m), 1.73 (1 H, dd, J=13.7, 3.1Hz), 1.48-1.65 (2 H, m), 1.28-1.33 (4 H, m), 1.17-1.25 (2 H, m),0.95-1.04 (2 H, m), 0.46-0.55 (3 H, m). Mass Spectrum (ESI) m/z=595(M+1).

Example 2022-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one

To a −78° C. solution of(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(764 mg, 1.211 mmol; Example 185, Step C) in THF (6 mL) under argon wasadded 1.0M lithium diisopropyl amide solution in THF (1.211 mL, 1.211mmol). The mixture was warmed to 0° C. for 30 minutes. The mixture wascooled to −78° C. and iodoethane (0.117 mL, 1.454 mmol) was added. Theresulting solution stirred at 0° C. for 1 hour. The mixture was quenchedwith sat. aq. NH₄Cl solution. The mixture was extracted with ethylacetate. The combined organic layers were washed with sat. aq. NaClsolution, dried over Na₂SO₄ and concentrated. The residue was purifiedby flash chromatography on silica gel (eluent: 5 to 25% ethylacetate/hexanes) to afford the title compound as a mixture ofdiastereomers.

Step B.(5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one

(5R,6S)-1-((S)-1-(Tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one(421 mg, 0.639 mmol; Example 202, Step A) was azeotroped with toluene(3×). THF (1.6 mL) was added. The mixture was sparged with argon for 5minutes and then cooled to 0° C. 1.0 M lithium diisopropylamide solutionin THF (1.246 mL, 1.246 mmol) was added dropwise. After 25 minutes,allyl bromide (0.166 mL, 1.917 mmol) was added dropwise. After 20minutes, the mixture was quenched with sat. aq. NH₄Cl solution. Themixture was extracted with ethyl acetate. The organic layer was washedwith sat. aq. NaCl solution, dried over Na₂SO₄, and concentrated. Theresidue was dissolved in THF (3 mL) and 1.0M tetrabutylammonium fluoridesolution in THF (2.335 mL, 2.335 mmol) was added. After stirringovernight, the mixture was partitioned between 5% aq. HCl and ethylacetate. The organic layer was washed with sat. aq. NaCl solution, driedover Na₂SO₄, and concentrated. The residue was purified by flashchromatography on silica gel (eluent: 20 to 50% ethyl acetate/hexanes)to afford the title compound as the more polar major diastereomer.

Step C.N-((2S)-2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(147 mg, 0.319 mmol; Example 202, Step B) andN-methylcyclopropanesulfonamide (129 mg, 0.958 mmol) were dissolved intoluene (2 mL). The mixture was evacuated and backfilled with argon(5×). Cyanomethylenetributylphosphorane (0.251 mL, 0.958 mmol) wasadded. The mixture was evacuated and backfilled with argon (5 X). Themixture was heated at 70° C. for 2 hours. The mixture was loaded ontosilica gel and the product was eluted with 5 to 75% ethylacetate/hexanes to afford the title compound.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained fromN-((2S)-2-((5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 202, Step C) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.54 (t, J=7.53 Hz, 3 H) 0.85-1.10(m, 7 H) 1.15-1.23 (m, 2 H) 1.51-1.65 (m, 1 H) 1.84-2.04 (m, 4 H)2.15-2.25 (m, 1 H) 2.25-2.38 (m, 2 H) 2.69-2.82 (m, 1 H) 2.87 (s, 3 H)2.93-3.10 (m, 2 H) 4.76 (d, J=10.37 Hz, 1 H) 6.84 (d, J=6.65 Hz, 1 H)6.91-6.97 (m, 1 H) 7.08-7.17 (m, 2 H) 7.20-7.29 (m, 4 H). Mass Spectrum(ESI) m/z=595.2 (M+1).

Example 2032-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-hydroxypiperidin-2-one

(5R,6S)-1-((S)-1-(Tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(1.100 g, 1.744 mmol; Example 185, Step C) was dissolved in THF (8.72mL) and sparged with argon for 5 minutes. The mixture was cooled to −78°C. and 1.0 M lithium bis(trimethylsilyl)amide solution in THF (2.093 mL,2.093 mmol) was added dropwise. After 30 minutes,peroxybis(trimethylsilane) (0.413 mL, 1.918 mmol) was added dropwise.After 1 hour, the cooling bath was removed. After stirring overnight,the mixture was quenched with sat. aq. NH₄Cl solution and extracted withethyl acetate. The organic layer was washed with sat. aq. NaCl solution,dried over Na₂SO₄, and concentrated. The residue was dissolved in EtOH(14 mL) and pyridine p-toluenesulfonate (131 mg, 0.523 mmol) was added.After 1 hour, the mixture was basified with sat. aq. NaHCO₃ solution.The mixture was partitioned between ethyl acetate and water. The organiclayer was washed with sat. aq. NaCl solution, dried over Na₂SO₄, andconcentrated. The residue was purified by flash chromatography on silicagel (40 g column, eluent: 5 to 50% ethylacetate/hexanes) to afford thetitle compound.

Step B.(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one

To a 0° C. solution of(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-hydroxypiperidin-2-one(476 mg, 0.736 mmol; Example 203, Step A) in THF (7.360 mL) was addedsodium hydride (58.9 mg, 1.472 mmol). After 30 minutes, iodomethane(0.092 mL, 1.472 mmol) was added. After 5 minutes, the cooling bath wasremoved. After 2 hours, the mixture was quenched with sat. aq. NH₄Clsolution. The mixture was partitioned between ethyl acetate and water.The organic layer was washed with sat. aq. NaCl solution, dried overNa₂SO₄, and concentrated to afford the title compound.

Step C.(3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one

A solution of(5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one(495 mg, 0.749 mmol; Example 203, Step B) in THF (7.49 mL) was spargedwith argon for 5 minutes and cooled to 0° C. 1.0 Mlithiumdiisopropylamide solution in THF (1.461 mL, 1.461 mmol) was addeddropwise. The internal temperature did not rise above 2° C. After 30minutes, allyl bromide (0.194 mL, 2.247 mmol) was added. The coolingbath was replaced with a room temperature water bath. After 70 minutes,the mixture was quenched with sat. aq. NH₄Cl solution and extracted withethyl acetate. The organic layer was washed with sat. aq. NaCl solution,dried over Na₂SO₄ and concentrated. The residue was purified by flashchromatography on silica gel (40 g column, eluent: 5 to 30% ethylacetate/hexanes) to afford the title compound as the more polardiastereomer.

Step D.(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methoxypiperidin-2-one

To a solution of(3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one(260 mg, 0.371 mmol; Example 203, Step C) in THF (1 mL) was added 1.0 Mtetrabutylammonium fluoride solution in THF (1.484 mL, 1.484 mmol).After stirring overnight, the mixture was partitioned between water andethyl acetate. Sat. aq. NH₄Cl solution was added to break up theemulsion. The organic layer was washed with sat. aq. NaCl solution,dried over Na₂SO₄, and concentrated. The residue was purified by flashchromatography on silica gel (12 g column, eluent: 35 to 100% ethylacetate/hexanes) to afford the title compound.

Step E.N—((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

To a solution of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methoxypiperidin-2-one(124 mg, 0.268 mmol; Example 203, Step D) in toluene (1.3 mL) was addedN-methylcyclopropanesulfonamide (109 mg, 0.804 mmol). The mixture wasevacuated and backfilled with argon (5×).Cyanomethylenetributylphosphorane (0.211 mL, 0.804 mmol) was added. Themixture was evacuated and backfilled with argon (5×). The mixture washeated in a 70° C. oil bath for 12 hours then cooled to room temperatureand stirred for 2 days at room temperature. The mixture was loaded ontosilica gel and the product was eluted with 20-60% ethyl acetate/hexanes.The residue was one more time purified by flash chromatography on silicagel (12 g column, eluent: 10 to 60% ethylacetate/hexanes) to afford thetitle compound.

Step F.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained fromN—((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxy-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 203, Step E) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.59 (t, J=7.53 Hz, 3 H) 1.02-1.05(m, 2 H) 1.16-1.27 (m, 2 H) 1.59-1.77 (m, 1 H) 1.85-1.99 (m, 2 H)2.22-2.40 (m, 1 H) 2.75 (d, J=13.30 Hz, 1 H) 2.84-2.98 (m, 6 H)3.03-3.16 (m, 2 H) 3.26 (d, J=15.65 Hz, 1 H) 3.52 (s, 3 H) 4.99 (d,J=10.76 Hz, 1 H) 6.91-6.97 (m, 2 H) 7.02 (s, 1 H) 7.10-7.20 (m, 2 H)7.22-7.31 (m, 3 H). Mass Spectrum (ESI) m/z=597.1 (M+1).

Example 2042-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-methyl-4-oxoheptan-3-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydroxy-6-methylheptan-3-yl)-3-methylpiperidin-2-one

To a solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(1.755 mmol) (Example 91, Step C) in THF (5 mL) at 0° C. was added 2 Misobutylmagnesium bromide (878 μL, 1.742 mmol) under N₂. The reactionwas allowed to warm to rt. After being stirred for 2 h at rt, thereaction was quenched with saturated NH₄Cl solution and extracted withEtOAc. The combined organic layers were washed (sat. aq. NaCl solution),dried over MgSO₄, filtered and the filtrate was concentrated underreduced pressure. The residue was purified by the flash chromatographyon silica gel (eluent: 15 to 35% EtOAc/Hexane, gradient elution) toprovide the title compound as a mixture of two diastereomers.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-6-methyl-4-oxoheptan-3-yl)-2-oxopiperidin-3-yl)aceticacid

To a rapidly stirring solution of 120 mg (0.239 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4-hydroxy-6-methylheptan-3-yl)-3-methylpiperidin-2-one(Example 204, Step A) in a mixture of 1.5 mL of water, 1.0 mL ofacetonitrile and 1.0 mL of CCl₄ was added sodium periodate (204 mg,0.995 mmol), followed by ruthenium(III) chloride hydrate (5.38 mg, 0.024mmol). After being stirred vigorously for 2 h, the reaction wasacidified (10% citric acid) and diluted with EtOAc. The reaction mixturewas filtered through Celite® (J.T. Baker, Phillipsberg, N.J.,diatomaceous earth) and the filtrate was extracted with EtOAc. Thecombined organic layers were washed with sat. NaCl solution, dried overNa₂SO₄, filtered and the filtrate was concentrated under reducedpressure. The residue was purified by the flash chromatography on silicagel (eluent: 10 to 20% iPrOH/hexane, gradient elution) to provide thetitle compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.64 (t, J=8.0 Hz, 3 H), 0.89 (d,J=8.0 Hz, 3 H), 0.92 (d, J=8.0 Hz, 3 H), 1.21 (m, 1 H), 1.39 (s, 3 H),1.82 (m, 1 H), 210-2.45 (m, 7 H), 2.87 (dd, J=16.0, 12 Hz, 2 H), 3.09(t, J=8.0 Hz, 1 H), 3.26 (m, 1 H), 4.44 (d, J=8.0 Hz, 1 H), 6.76 (d,J=8.0 Hz, 1 H), 6.90-7.02 (m, 3 H), 7.08 (t, J=8.0 Hz, 1 H), 7.12 (d,J=8.0 Hz, 1 H), 7.23 (d, J=8.0 Hz, 2 H); MS (ESI) 531.1 [M+H]⁺.

Example 2052-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. Diethyl ethylsulfonylmethylphosphonate

To a stirred solution of diethyl ethylthiomethylphosphonate (Aldrich,St. Louis, Mo.) (0.912 mL, 4.71 mmol) in dichloromethane (47.1 mL) at 0°C. was added meta-chloroperoxybenzoic acid (2.63 g, 15.2 mmol). Thereaction mixture was stirred at 25° C. for 24 hours. The reactionsolvent was removed in vacuo, the crude material was diluted withdiethyl ether, and was then washed with saturated sodium bicarbonate(3×). The organic layer was dried over Na₂SO₄, filtered and the filtratewas concentrated under reduced pressure to provide the title compound asan off-white solid.

Step B.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S,E)-1-(ethylsulfonyl)pent-1-en-3-yl)-3-methylpiperidin-2-one

To a stirred solution of diethyl ethylsulfonylmethylphosphonate (153 mg,0.625 mmol; Example 202, Step A) in THF (2.60 mL) at −78° C. was addedbutyllithium (177 μL, 0.443 mmol). After 30 minutes, a solution of(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal(135 mg, 0.260 mmol; Example 150, Step D) in THF (0.50 mL) was added.The reaction was stirred for 15 minutes at −78° C. and was then stirredat 25° C. for 3 hours. The reaction was partitioned between saturatedammonium chloride and EtOAc (2×), and then the combined organic layerswere dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. Purification of the residue by flash chromatography onsilica gel (4 g column, eluent: 0 to 40% EtOAc/hexanes) provided thetitle compound as an off-white solid.

Step C.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S)-1-(ethylsulfonyl)pentan-3-yl)-3-methylpiperidin-2-one

To a solution of(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S,E)-1-(ethylsulfonyl)pent-1-en-3-yl)-3-methylpiperidin-2-one(65.0 mg, 0.107 mmol; Example 205, Step B) in 1,2-dichloroethane (1.07mL) at 25° C. was added Crabtree's catalyst (7.74 mg, 9.61 μmol). Thereaction system (a hydrogenation bomb) was flushed with hydrogen gas 3×,pressurized with hydrogen at 3447.38 kilopascal, and the reaction wasstirred at 25° C. for 24 hours. The reaction mixture was filteredthrough celite, washed with DCM, and concentrated under reduced pressureto yield the title compound as an off-white solid.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a stirred solution of(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S)-1-(ethylsulfonyl)pentan-3-yl)-3-methylpiperidin-2-one(70.0 mg, 0.115 mmol; Example 202, Step C) in THF (1.15 mL) at 25° C.was added a solution of Jones' Reagent (chromium (VI) oxide) (138 μL,0.172 mmol) and the reaction mixture was stirred for 1 hour. Thereaction mixture was partitioned between water and EtOAc (2×), and thenthe combined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification of theresidue by reverse phase high-pressure liquid chromatography (Eclipsecolumn (Agilient Technologies, Santa Clara, Calif.), eluent: 30-75%acetonitrile/water) provided the title compound as an off-white solid.

¹H NMR (500 MHz, CDCl₃) δ ppm 0.58 (t, J=7.34 Hz, 3 H), 1.43 (t, J=7.46Hz, 3 H), 1.49 (s, 3 H), 1.51-1.57 (m, 1 H), 1.86 (dt, J=14.55, 7.40 Hz,1 H), 1.98 (dd, J=12.84, 5.75 Hz, 1 H), 2.04 (dd, J=13.94, 2.45 Hz, 1H), 2.16-2.23 (m, 2 H), 2.76 (d, J=15.16 Hz, 1 H), 2.97-3.04 (m, 5 H),3.11-3.20 (m, 1 H), 3.24-3.38 (m, 1 H), 4.58 (d, J=10.51 Hz, 1 H), 6.75(d, J=7.58 Hz, 1 H), 6.95 (s, 1 H), 7.05 (d, J=4.89 Hz, 2 H), 7.09-7.14(m, 1 H), 7.14-7.18 (m, 1 H), 7.23-7.27 (m, 2 H); MS (ESI) 554.2 [M+H]⁺.

Example 2062-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. S-(diisopropoxyphosphoryl)methyl ethanethioate

To a stirred solution of diisopropyl bromomethylphosphonate (5.00 g,19.3 mmol) in N,N-dimethylformamide (15.4 mL) was added potassiumthioacetate (3.75 g, 32.8 mmol) followed by tetrabutylammonium iodide(0.36 g, 0.97 mmol). The reaction mixture was stirred at 85° C. for 2.5hours. The reaction mixture was cooled and partitioned between water andEtOAc (3×) and the layers were separated. The combined organic layerswere dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. Purification of the residue by flash chromatography onsilica gel (24 g column, eluent: 0 to 90% EtOAc/hexanes) provided thetitle compound as an off-white solid.

Step B. Diisopropyl isopropylthiomethylphosphonate

To a stirred solution of S-(diisopropoxyphosphoryl)methyl ethanethioate(1.00 g, 3.93 mmol; Example 206, Step A) in methanol (39.3 mL) at 0° C.was added sodium methoxide (7.87 mL, 3.93 mmol), followed by2-bromopropane (0.44 mL, 4.72 mmol). The reaction was stirred at 25° C.for 16 hours. The reaction solvent was removed in vacuo and the crudematerial was partitioned between water and EtOAc (2×) and the layerswere separated. The aqueous layer was extracted with EtOAc and thecombined organic layers were dried over Na₂SO₄, filtered and thefiltrate was concentrated under reduced pressure. Purification of theresidue by flash chromatography on silica gel (40 g column, eluent: 0 to75% DCM/hexanes) provided the title compound as an off-white solid.

Step C. Diisopropyl isopropylsulfonylmethylphosphonate

Diisopropyl isopropylthiomethylphosphonate was converted to the titlecompound by the procedure described in Example 205, Step A and wasisolated as an off-white solid.

Step D.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S,E)-1-(isopropylsulfonyl)pent-1-en-3-yl)-3-methylpiperidin-2-one

(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 150, Step D) was converted to the title compound as describedin Example 205, Step B and was isolated as an off-white solid.

Step E.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S)-1-(isopropylsulfonyl)pentan-3-yl)-3-methylpiperidin-2-one

(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S,E)-1-(isopropylsulfonyl)pent-1-en-3-yl)-3-methylpiperidin-2-onewas converted to the title compound as described in Example 205, Step Cand was isolated as an off-white solid.

Step F.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1-((S)-1-(isopropylsulfonyl)pentan-3-yl)-3-methylpiperidin-2-onewas converted to the title compound as described in Example 205, Step Dand was isolated as an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.55 (t, J=6.55 Hz, 3 H), 1.43 (d, J=6.26Hz, 6 H), 1.49 (br. s., 3 H), 1.81-1.96 (m, 1 H), 1.98-2.10 (m, 2 H),2.14-2.25 (m, 1 H), 2.27-2.41 (m, 1 H), 2.77 (d, J=15.85 Hz, 2 H),2.95-3.07 (m, 3 H), 3.09-3.19 (m, 2 H), 3.19-3.31 (m, 1 H), 4.65 (d,J=10.56 Hz, 1 H), 6.75 (d, J=7.24 Hz, 1 H), 6.96 (s, 1 H), 7.01-7.10 (m,2 H), 7.12 (d, J=7.63 Hz, 1 H), 7.14-7.19 (m, 1 H), 7.23-7.27 (m, 2 H);MS (ESI) 568.2 [M+H]⁺.

Example 2072-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

(2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 150, Step D) withdiisopropyl(cyclopropylmethylsulfonyl)methylphosphonate (prepared as anoff-white solid in analogy to the procedure of Example 206 steps A andB) were converted to the title compound by the sequence as described inExample 205. The title compound is an off-white solid.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.39-0.48 (m, 2 H), 0.56 (t, J=7.10 Hz, 3H), 0.74-0.86 (m, 2 H), 1.13-1.25 (m, 1 H), 1.48 (br. s., 3 H),1.51-1.59 (m, 1 H), 1.79-1.94 (m, 1 H), 1.97-2.11 (m, 2 H), 2.13-2.24(m, 1 H), 2.24-2.42 (m, 1 H), 2.78 (d, J=14.87 Hz, 1 H), 2.92 (d, J=5.28Hz, 2 H), 2.97-3.11 (m, 3 H), 3.16 (t, J=11.54 Hz, 1 H), 3.21-3.33 (m, 1H), 4.62 (d, J=10.37 Hz, 1 H), 6.75 (d, J=7.04 Hz, 1 H), 6.96 (br. s., 1H), 7.01-7.20 (m, 4 H), 7.21-7.27 (m, 2 H); MS (ESI) 580.2 [M+H]⁺.

Example 2082-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-2-one

To a solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(84 mg, 0.189 mmol; Example 91, Step C), ethyl 4-aminobutyratehydrochloride (127 mg, 0.756 mmol) and acetic acid (3 drops) in DCE/MeOH(3/1, 4.0 mL) was added sodium triacetoxyhydroborate (200 mg, 0.945mmol) at 25° C. After being stirred at 25° C. for 18 h, the reaction wasquenched by adding ice-cold saturated aqueous NaHCO₃ solution and wasextracted with DCM. The combined organic layers were washed (1×sat. aq.NaCl solution) and concentrated under reduced pressure. The residue waspurified by reverse phase preparatory HPLC (acetonitrile in water with0.1% TFA, gradient elution) to give the title compound as a white solid.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-3-yl)aceticacid

The title compound was obtained from((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(2-oxopyrrolidin-1-yl)butan-2-yl)piperidin-2-one(Example 208, Step A) by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J=8.0 Hz, 3 H), 1.52 (s, 3H), 1.65 (m, 1 H), 1.90-2.28 (m, 5 H), 2.58 (m, 2 H), 2.75 (d, J=12.0Hz, 1 H), 3.02 (d, J=12.0 Hz, 1 H), 3.08 (m, 3 H), 3.47 (m, 2 H), 3.99(m, 1 H), 4.37 (d, J=12.0 Hz, 1 H), 6.72 (d, J=8.0 Hz, 1 H), 6.89-7.00(m, 3 H), 71.0 (t, J=8.0 Hz, 1 H), 7.16 (m, 1 H), 7.26 (d, J=4.0 Hz, 2H); MS (ESI) 531.1 [M+H]⁺.

Example 2092-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid—TFA Salt

Step A.(3S,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-yl)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

To a solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(100 mg, 0.224 mmol; Example 91, Step C) in DCE (2 mL) was added(1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptane (Butora, G.; Goble, S.;Pastemak, A.; Yang, L.; Zhou, C.; Moyes, C. U.S. Patent Publication No.2008/0081803 (50 mg, 0.504 mmol) followed by sodiumtriacetoxyborohydride (95 mg, 0.448 mmol) and acetic acid (1.2 μL, 0.022mmol). After stirring overnight, the mixture was quenched with sat. aq.NaHCO₃ solution. The mixture was extracted with ethyl acetate (2×). Thecombined organic layers were washed with sat. aq. NaCl solution, driedover Na₂SO₄, and concentrated. The residue was purified by flashchromatography on silica gel (eluent: 1 to 5% methanol/dichloromethane)to afford the title compound.

Step B.2-((3R,5R,6S)-1-((S)-1-((1R,4R)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid—TFA Salt

To a solution of(3S,5R,6S)-1-((S)-1-((1R,4R)-2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)butan-2-yl)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(87 mg, 0.17 mmol; Example 209, Step A) in THF (0.8 mL), water (0.4 mL),and t-butanol (0.4 mL) was added 4-methylmorpholine N-oxide (29 mg, 0.25mmol) and 5 drops of 4% aq. OsO₄. After 18 hours, Jones' Reagent (0.20mL) was added. After 24 hours, 50 mL water was added to the mixture andthen the mixture was extracted with ethyl acetate (3×). The combinedorganic layers were washed with water, dried over Na₂SO₄ andconcentrated. The residue was purified by reverse phase preparatory HPLC(column: Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.;eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) toafford the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.17 (m, 3 H) 1.30-1.53 (m, 5H) 1.75-1.95 (m, 1 H) 2.03-2.17 (m, 2 H) 2.18-2.32 (m, 2 H) 2.37-2.54(m, 1 H) 2.59-2.79 (m, 2 H) 2.80-2.94 (m, 1 H) 3.17-3.32 (m, 1 H)3.73-3.93 (m, 2 H) 3.95-4.14 (m, 1 H) 4.40-4.55 (m, 2 H) 4.56-4.65 (m, 1H) 4.90-5.23 (m, 1 H) 6.58-6.73 (m, 1 H) 6.93-7.02 (m, 1 H) 7.04-7.09(m, 1 H) 7.14 (d, J=7.43 Hz, 2 H) 7.23-7.36 (m, 3 H). Mass Spectrum(ESI) m/z=545.2 (M+1).

Example 2102-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R)-3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((2S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid

To a −78° C. solution of oxalyl chloride (0.166 mL, 0.332 mmol) indichloromethane (2 mL) was added dimethylsulfoxide (0.047 mL, 0.663mmol) dropwise. After ten minutes,2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (140 mg, 0.301 mmol; Example 185) in dichloromethane (2 mL) wasadded dropwise. After 15 minutes, triethylamine (0.210 mL, 1.507 mmol)was added dropwise. The mixture was warmed to 0° C. for 10 minutes andthen quenched with 10% aq. citric acid. The mixture was diluted withwater and extracted with dichloromethane (2×).

The combined organic layers were washed with sat. aq. NaCl solution,dried over anhydrous Na₂SO₄, and concentrated to afford the titlecompound.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-1-(3-methylmorpholino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid (960 mg, 2.076 mmol; Example 210, Step A) in 1,2-dichloroethane (15mL) was added 3-methylmorpholine (Enamine Ltd, Kiev, Ukraine) (0.471 mL,4.15 mmol) and sodium triacetoxyborohydride (880 mg, 4.15 mmol).

After stirring overnight, the mixture was quenched with sat. aq. NH₄Clsolution. The mixture was extracted with dichloromethane (2×). Thecombined organic layers were washed with sat. aq. NaCl solution, driedover anhydrous Na₂SO₄, and concentrated. The residue was purified byflash chromatography on silica gel (eluent: 1 to 10%methanol/dichloromethane) to afford the title compound as the majordiastereomer. Stereochemistry of the 3-morpholine stereocenter isunknown.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, J=7.53 Hz, 3 H) 1.02 (d,J=6.26 Hz, 3 H) 1.46 (s, 3 H) 1.54-1.68 (m, 1 H) 1.85-1.98 (m, 2 H)2.01-2.06 (m, 1 H) 2.15-2.28 (m, 2 H) 2.58-2.89 (m, 4 H) 2.97-3.13 (m, 2H) 3.26-3.37 (m, 1 H) 3.55-3.71 (m, 2 H) 3.77-3.85 (m, 1 H) 3.90 (d,J=10.96 Hz, 1 H) 4.78 (d, J=10.17 Hz, 1 H) 6.77 (dt, J=7.48, 1.54 Hz, 1H) 6.82-6.96 (m, 2 H) 6.97-7.02 (m, 1 H) 7.08-7.30 (m, 4 H). MassSpectrum (ESI) m/z=547.2 (M+1).

Example 2112-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(thiomorpholino-1,1-dioxide)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid (0.101 g, 0.219 mmol; Example 210, Step A) in 1,2-dichloroethane (3mL) was added thiomorpholine 1,1-dioxide (0.128 g, 0.947 mmol), sodiumtriacetoxyborohydride (0.093 g, 0.438 mmol), and 2 drops of acetic acid.After stirring for 2 days, the mixture was quenched with water. Themixture was extracted with ethyl acetate (2×). The combined organiclayers were washed with sat. aq. NaCl solution, dried over anhydrousNa₂SO₄, and concentrated. The colorless film was purified by reversephase preparatory HPLC (column: Gemini-NX C₁₈ 5 um column; Phenomonex,Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA,over 20 minutes). Fractions containing the product were transferred to aseparatory funnel and sat. aq. NaHCO₃ solution and dichloromethane wereadded. The aqueous layer was back extracted with dichloromethane. Thecombined organic layers were washed with sat. aq. NaCl solution, driedover anhydrous Na₂SO₄, and concentrated to afford the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.66 (t, J=7.14 Hz, 3 H) 1.46 (s, 4H) 1.53-1.64 (m, 1 H) 1.78-1.91 (m, 1 H) 1.99-2.26 (m, 5 H) 2.77 (d,J=15.06 Hz, 1 H) 2.91-3.17 (m, 9 H) 4.41 (d, J=9.98 Hz, 1 H) 6.73 (d,J=7.43 Hz, 1 H) 6.90-6.91 (m 1 H) 7.09-7.22 (m, 2 H) 7.23-7.30 (m, 4 H).Mass Spectrum (ESI) m/z=581.2 (M+1).

Example 2122-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-difluoroazetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid (99 mg, 0.215 mmol; Example 210, Step A) in 1,2-dichloroethane (3mL) was added 3,3-difluoroazetidine hydrochloride (55.7 mg, 0.430 mmol)followed by sodium triacetoxyborohydride (91 mg, 0.430 mmol). Afterstirring overnight, the mixture was quenched with water. The mixture wasextracted with ethyl acetate (2×). The combined organic layers werewashed with sat. aq. NaCl solution, dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by reverse phase preparatory HPLC(column: Gemini-NX C₁₈ 5 um column; Phenomonex, Torrance, Calif.;eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes).Fractions containing the product were transferred to a separatory funneland sat. aq. NaHCO₃ and dichloromethane were added. The aqueous layerwas back extracted with dichloromethane. The combined organic layerswere washed with sat. aq. NaCl solution, dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated to afford the title compound.

¹H NMR (400 MHz, ACETONITRILE-d₃) δ ppm 0.48 (t, J=7.53 Hz, 3 H) 1.32(s, 3 H) 1.46-1.62 (m, 1 H) 1.68-1.82 (m, 1 H) 1.90-1.98 (m, 2 H)2.01-2.05 (m 1 H) 2.13-2.23 (m, 1 H) 2.40 (dd, J=12.42, 4.99 Hz, 1 H)2.67-2.78 (m, 1 H) 2.82-2.92 (m, 1 H) 3.16-3.29 (m, 1 H) 3.43-3.70 (m, 4H) 4.55 (d, J=10.37 Hz, 1 H) 6.96 (td, J=4.35, 1.66 Hz, 1 H) 7.03-7.10(m, 1 H) 7.12-7.21 (m, 4 H) 7.23-7.31 (m, 2 H). Mass Spectrum (ESI)m/z=539.0 (M+1).

Example 2132-((3R,5R,6S)-1-((2S)-1-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid (99 mg, 0.215 mmol; Example 210, Step A) in DCE (3 mL) was added48.7 mg (0.43 mmol) of 8-oxa-3-azabicyclo[3.2.1]octane (Connolly, T.;Considine, J.; Ding, Z.; Forsatz, B.; Jennings, M.; MacEwan, M.; McCoy,K.; Place, D.; Sharma, A.; Sutherland, K. Organic Process Research &Development. 2010, 14(2), 459-465. Note: reference is for the HCl Salt).Sodium triacetoxyborohydride (91 mg, 0.430 mmol) was added followed byacetic acid (1.2 μL, 0.022 mmol). After stirring overnight, the mixturewas partitioned between 5% aq. HCl and ethyl acetate. The organic layerwas washed with sat. aq. NaCl solution, dried over Na₂SO₄, andconcentrated. The residue was purified by reversed phase preparatoryHPLC (eluent: 0-100% MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes).Fractions containing the product were transferred to a separatory funneland sat. aq. NaHCO₃ and dichloromethane were added. The aqueous layerwas back extracted with dichloromethane. The combined organic layerswere washed with sat. aq. NaCl solution, dried over anhydrous Na₂SO₄,filtered and the filtrate was concentrated to afford the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.37-0.53 (m, 3 H) 1.48-1.58 (m, 4H) 1.83-2.15 (m, 7 H) 2.18-2.31 (m, 2 H) 2.50 (s, 2 H) 2.60 (d, J=10.76Hz, 1 H) 2.70 (d, J=15.65 Hz, 1 H) 2.96-3.17 (m, 4 H) 4.29-4.42 (m, 2 H)4.55 (d, J=10.56 Hz, 1H) 6.65 (dt, J=7.68, 1.44 Hz, 1 H) 6.94-7.02 (m, 1H) 7.06-7.13 (m, 1 H) 7.14-7.21 (m, 1 H) 7.21-7.33 (m, 4 H). MassSpectrum (ESI) m/z=559.2 (M+1).

Example 2142-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3,3-dimethylmorpholino)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid (70 mg, 0.151 mmol; Example 210, Step A) in DCE (3 mL) was added45.9 mg (0.303 mmol) of 3,3-dimethylmorpholine hydrochloride (Cottle,D.; Jeltsch, A.; Stoudt, T.; Walters, D. Journal of Organic Chemistry.1946, 11(3), 286-91.; Note: reference is for the free base) and sodiumtriacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring overnight,the mixture was diluted with sat. aq. NH₄Cl solution. The mixture wasextracted with DCM (2×). The combined organic layers were washed withsat. aq. NaCl solution, dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated. The residue was purified by preparative thinlayer chromatography on silica gel (eluent: 50% ethyl acetate/hexanes).The product containing fractions were pooled, concentrated andrepurified by preparative thin layer chromatography on silica gel(eluent: 10% MeOH/DCM) to afford the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.47-0.51 (m 3 H) 0.92-1.07 (m, 6H) 1.26 (s, 3 H) 1.44-1.48 (m 6 H) 1.83-1.98 (m, 2H) 1.99-2.08 (m, 1 H)2.14-2.52 (m, 3 H) 3.34-3.37 (m 1 H) 3.42-3.52 (m, 1 H) 3.57-3.69 (m, 1H) 3.87 (d, J=10.96 Hz, 1 H) 4.86 (d, J=11.15 Hz, 1 H) 6.77 (d, J=7.43Hz, 1 H) 6.94-7.05 (m, 1 H) 7.08-7.30 (m, 6 H). Mass Spectrum (ESI)m/z=561.3 (M+1).

Example 2152-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid (70 mg, 0.151 mmol; Example 210, Step A) in DCE (3 mL) was added53.8 mg (0.303 mmol) of 3-(trifluoromethyl)azetidin-3-ol hydrochloride(U.S. patent application publication no 2007/0275930) and sodiumtriacetoxyborohydride (64.2 mg, 0.303 mmol). After stirring for 18hours, the mixture was partitioned between water and DCM. The aqueouslayer was washed with DCM. The combined organic layers were washed withsat. aq. NaCl solution, dried over anhydrous Na₂SO₄, filtered and thefiltrate was concentrated. The residue was purified by preparative thinlayer chromatography on silica gel (eluent: 50% ethyl acetate/hexanes)to afford the title compound.

¹H NMR (400 MHz, MeOH) δ ppm 0.51 (t, J=7.43 Hz, 3 H) 1.36 (s, 3 H)1.50-1.66 (m, 1 H) 1.71-1.86 (m, 1 H) 2.09-2.26 (m, 2 H) 2.38 (dd,J=12.52, 3.91 Hz, 1 H) 2.52-2.64 (m, 1 H) 2.75 (br. s., 1 H) 2.93 (d,J=14.87 Hz, 1 H) 3.11-3.27 (m, 2 H) 3.28-3.43 (m, 3 H) 3.66-3.79 (m, 2H) 4.62 (d, J=10.56 Hz, 1 H) 6.86-6.98 (m, 1 H) 7.03 (s, 1 H) 7.09-7.22(m, 4 H) 7.27 (d, J=7.24 Hz, 2 H). Mass Spectrum (ESI) m/z=587.2 (M+1).

Example 2162-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methyl(oxetan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid—Ammonium Salt

To a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)aceticacid (201 mg, 0.434 mmol; Example 210 Step A) in DCE (3 mL) was addedmethylamine hydrochloride (117 mg, 1.736 mmol) followed by sodiumtriacetoxyborohydride (184 mg, 0.868 mmol). After 4 hours, the mixturewas diluted with methanol and DCM, filtered, and concentrated. Theresidue was purified by flash chromatography on silica gel (eluent:20-100% ethylacetate/hexanes followed by 6:1:0.1 DCM:MeOH:NH₄OH) toafford the title compound.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methyl(oxetan-3-yl)amino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of oxetan-3-one (17.78 mg, 0.247 mmol) in DCE (3 mL) wasadded2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylamino)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid ammonium salt (61 mg, 0.123 mmol) obtained in Step A followed bysodium triacetoxyborohydride (78 mg, 0.370 mmol) and 3 drops AcOH. After45 minutes, 3 ml MeOH and oxetan-3-one (12 mg, 0.17 mmol) were added.After stirring overnight, oxetan-3-one (12 mg, 0.17 mol) and sodiumtriacetoxyborohydride (60 mg, 0.32 mmol) were added. After 24 hours, themixture was diluted with methanol and evaporated onto silica gel. Thesolid was purified by flash chromatography on silica gel (eluent: 0 to100% [6:1:0.1 DCM/MeOH/NH₄OH] in DCM). The product containing fractionswere pooled, concentrated and repurified by preparative thin layerchromatography on silica gel (eluent: 10% MeOH/DCM) to afford the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.51 (t, J=7.53 Hz, 3 H) 0.78-0.93(m, 1 H) 1.14-1.32 (m, 3 H) 1.87-1.95 (m 1 H) 2.04 (d, J=13.30 Hz, 1 H)2.12 (s, 3 H) 2.19-2.38 (m, 2 H) 2.71 (d, J=15.65 Hz, 1 H) 2.99-3.15 (m,3 H) 3.44-3.60 (m, 1 H) 4.44-4.81 (m, 6 H) 6.81 (d, J=7.24 Hz, 1 H)6.94-7.04 (m, 2 H) 7.09-7.21 (m, 2 H) 7.23-7.31 (m, 3H). Mass Spectrum(ESI) m/z=533.2 (M+1).

Example 2172-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxooxazolidin-3-yl)butan-2-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-hydroxyethyl)amino)butan-2-yl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-((2-hydroxyethyl)amino)butan-2-yl)-3-methylpiperidin-2-one

(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(180 mg, 0.405 mmol; Example 91, Step C) in ClCH₂CH₂Cl (1 mL) wasstirred with sodium triacetoxyborohydride (172 mg, 0.81 mmol),ethanolamine (0.04 mL, 0.73 mmol) and acetic acid (0.06 mL, 1.013 mmol)at ambient temperature for 18 h, by which time analysis by LC-MSindicated the presence of the desired product. The mixture waspartitioned between saturated NaHCO₃ and CH₂Cl₂. The organic layer wasconcentrated, and the residue purified by chromatography (silica gel,hexane/EtOAc, then EtOAc/MeOH, up to 15%) to afford the title compoundsas a 1:1 mixture of two diastereomers. MS (ESI) m/z=489 (M+1).

Step B.3-((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)oxazolidin-2-oneand3-((R)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)oxazolidin-2-one

A mixture of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-hydroxyethyl)amino)butan-2-yl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-((2-hydroxyethyl)amino)butan-2-yl)-3-methylpiperidin-2-one(60 mg, 0.123 mmol; Example 217, Step A) was mixed with1,1′-carbonyldiimidazole (99 mg, 0.61 mmol) and1,8-diazabicyclo[5.4.0]undec-7-ene (37 mg, 0.245 mmol) in 1,4 dioxane (1mL). The mixture was heated to 100° C. in an oil bath for 18 h. Themixture was allowed to cool to ambient temperature, was diluted withEtOAc and washed with water three times. The crude product was thenfiltered through a pad comprised of silica gel and Na₂SO₄ to give thetitle compound, which was used without further purification. MS (ESI)m/z=515 (M+1).

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S)-1-(5-methyl-2-oxooxazolidin-3-yl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from the mixture obtained in Example217, Step B by a procedure similar to the one described in Example 71,Step F. A mixture of two diastereomers was isolated, which was thenfurther purified by chiral separation to afford the title compound(250×30 mm Chiralpak® IC column (Chiral Technologies, Inc., WestChester, Pa., USA) with 32 g/min MeOH (20 mM NH₃)).

¹H NMR (CDCl₃, 500 MHz) δ ppm 0.57 (t, 3H), 1.50 (s, 3H), 1.70 (m, 1H),1.90 (m, 1H), 2.00 (m, 1H), 2.25 (t, 1H), 2.78 (br, 1H), 2.98 (br, 1H),3.13 (m, 3H), 3.62 (m, 2H), 3.85 (br, 1H), 4.40 (m, 3H), 6.67 (m, 1H),6.93 (s, 1H), 6.99 (br, 2H), 7.14 (m, 2H), 7.24 (m, 2 H). MS (ESI)m/z=533 (M+1).

Example 2182-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(60 mg, 0.134 mmol; Example 91, Step C) was mixed withtriphenylphosphine (42 mg, 0.161 mmol), 2-hydroxypyridine (14.1 mg.0.148 mmol) and diisopropyl azodicarboxylate (0.029 mL, 0.148 mmol) intoluene in an oven-dried 3-neck roundbottom flask. The mixture wasstirred at ambient temperature for 18 h under nitrogen. Solvent wasevaporated. The residue was then purified by chromatography (silica gel,hexane/EtOAc, 1:0 to 2:3) to afford the title compound as a colorlessoil.

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxopyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)aceticacid

To a 25 mL roundbottom flask charged with(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(35 mg, 0.067 mmol; Example 218, Step A) was added THF, water (until thereaction became and remained cloudy with gentle stirring), and tBuOH(until the cloudy reaction became translucent). 4-Methylmorpholine4-oxide monohydrate (13.6 mg, 0.10 mmol) was added followed by osmiumtetroxide, 4 wt. %, in water (0.016 mL, 0.067 mmol). The reaction wasallowed to stir at ambient temperature for 16 h to complete theformation of the diol. To the resulting mixture was added Jones reagent(70 μL) at ambient temperature and stirring was continued for 18 h. Thereaction was quenched with water, diluted with EtOAc, and extracted withadditional EtOAc (3×8 mL). The combined organic layers were washed withwater, dried over MgSO₄, filtered and the filtrate was concentrated. Thelight greenish residue was purified by preparative HPLC to afford thetitle compound.

¹H NMR (CDCl₃, 400 MHz) δ ppm 0.53 (t, 3H), 1.43 (s, 3H), 1.68 (m, 1H),1.85 (t, 1H), 2.03 (m, 2H), 2.65 (m, 1H), 2.91 (m, 1H), 3.30 (m, 2H),3.72 (m, 1H), 4.25 (m, 1H), 4.42 (m, 1H), 6.71 (m, 4H), 7.70 (m, 4H),7.26 (m, 2H), 7.51 (m, 1H), 7.77 (m, 1H). Mass spectrum (ESI) m/z=541(M+1).

Example 2192-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)aceticacid

2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(2-oxo-5-(trifluoromethyl)pyridin-1(2H)-yl)butan-2-yl)piperidin-3-yl)aceticacid was prepared using the procedure described for example 218 by using2-hydroxy-5-(trifluoromethyl)pyridine, and tri-n-butylphosphine,azodicarboxylic dipiperidine in Step A.

¹H NMR (CDCl₃, 500 MHz) δ ppm 0.54 (t, 3H), 1.42 (s, 3H), 1.60 (m, 1H),1.78 (m, 1H), 2.01 (m, 2H), 2.77-2.93 (m, 2H), 3.13 (m, 1H), 3.42 (m,1H), 3.81 (m, 1H), 4.32 (m, 2H), 6.50 (m, 1H), 6.71 (m, 1H), 6.77 (m,1H), 6.91 (br, 2H), 7.03 (m, 1H), 7.11 (m, 1H), 7.23 (m, 2H), 7.69 (m,2H). Mass spectrum (ESI) m/z=609 (M+1).

Example 220(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(pyridin-3-yloxy)butan-2-yl)piperidin-2-one

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(pyridin-2-yloxy)butan-2-yl)piperidin-2-one(10 mg) was prepared as described for example 218 using 3-hydroypyridinein place of 2 hydroxypyridine.

¹H NMR (MeOH-d₄, 500 MHz) δ ppm 0.62 (m, 3H), 1.27 (s, 3H), 1.70 (m,1H), 1.97 (m, 1H), 2.18 (m, 2H), 2.59 (m, 1H), 2.96 (m, 1H), 3.44 (m,2H), 4.11 (m, 1H), 4.58 (m, 1H), 4.70 (m, 1H), 6.97 (m, 1H), 7.06 (m,1H), 7.15-7.28 (m, 6H), 7.81 (m, 1H), 7.98 (m, 1H), 8.37 (m, 1H), 8.56(s, 1H). Mass spectrum (ESI) m/z=541 (M+1).

Example 2212-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)aceticacid (Isomer 1)

Step A.(3S,5R,6S)-3-allyl-1-((3S)-7-((tert-butyldimethylsilyl)oxy)-4-hydroxyheptan-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

The Grignard reagent derived from of(3-bromopropoxy)(tert-butyl)dimethylsilane was prepared on 1.8 mmolscale according to Minguez, et al. Biorg. Med. Chem. 11, 3335, 2003 as agray solution in THF (˜3 mL). About 1.5 mL of the Grignard regent wasadded slowly to a solution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(100 mg, 0.22 mmol; Example 91, Step C) in THF (1 mL) at ambienttemperature. After 2 h, the reaction was diluted in ethyl acetate andwashed with saturated ammonium chloride solution followed by sat. aq.NaCl solution. The organic layer was dried over sodium sulfate andconcentrated. Purification by silica chromatography eluting with ethylacetate/hexane provided the title compound as a mixture ofdiastereomers.

¹H NMR (400 MHz, CHLOROFORM-d) representative signals:

major diastereomer δ ppm 1.17 (s, 3H), 4.25 (d J=10.6 Hz, 1H).

minor diastereomer δ ppm 1.21 (s, 3H), 4.37 (d, J=10.6 Hz, 1H).

Mass Spectrum (ESI) m/z=618.4 (M+1).

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4,7-dihydroxyheptan-3-yl)-3-methylpiperidin-2-one

A solution of(3S,5R,6S)-3-allyl-1-((3S)-7-(tert-butyldimethylsilyloxy)-4-hydroxyheptan-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(127 mg, 0.21 mmol; Example 221, Step A) in THF (1.5 mL) was treatedwith tetrabutylammonium fluoride (0.62 mL 1M in THF, 0.62 mmol) atambient temperature for 1.5 hours. The solvent was removed under vacuum.Purification by silica chromatography eluting with ethyl acetate/hexaneprovided the title compound as a mixture of diastereomers.

¹H NMR (400 MHz, CHLOROFORM-d) representative signals:

major diastereomer δ ppm 1.15 (s, 3H), 4.26 (d J=10.6 Hz, 1H),

minor diastereomer δ ppm 1.20 (s, 3H), 4.31 (d, J=10.6 Hz, 1H).

Mass Spectrum (ESI) m/z=504.3 (M+1).

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S)-tetrahydrofuran-2-yl)propyl)piperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R)-tetrahydrofuran-2-yl)propyl)piperidin-2-one

A solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4,7-dihydroxyheptan-3-yl)-3-methylpiperidin-2-one(55 mg, 0.11 mmol; Example 221, Step B) and triphenylphosphine (57.2 mg,0.22 mmol) in dichloromethane (2 mL) was treated with (E)-diethyldiazene-1,2-dicarboxylate (0.033 ml, 0.22 mmol) at ambient temperaturefor 2 hours. Purification by silica chromatography eluting with ethylacetate/hexane provided one of the title compounds as the majordiastereomer as the first eluting compound followed by the minordiastereomer.

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-2-one(Major Diastereomer; First Eluting Compound)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.65 (t, J=7.43 Hz, 3H) 1.20 (s,3H) 1.51-1.58 (m, 3H), 1.71 (m, 3H), 1.83-1.97 (m, 4H), 2.54-2.57 (dd,J=7.53, 3.62 Hz, 2H), 3.08-3.14 (ddd, J=13.01, 10.47, 3.72 Hz, 1H),3.53-3.58 (m, 2H), 3.73-3.77 (m, 1H), 4.30 (d, J=10.56 Hz, 1H), 5.08 (s,1H), 5.11 (d, J=4Hz, 1H), 5.74-5.84 (m, 1H), 6.62-6.64 (d, J=8 Hz, 1 H),6.86 (s, 3H), 7.02 (t, J=8 Hz, 1H), 7.04-7.09 (s, 1H), 7.15 (d, J=4Hz,2H). Mass Spectrum (ESI) m/z=486.3 (M+1).

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-2-one(Minor Diastereomer; Second Eluting Compound)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.47 (t, J=7.53 Hz, 3H), 1.10-1.21(m, 4H), 1.36-1.46 (m, 1H), 1.51 (s, 1H), 1.73-2.06 (m, 5H), 2.45-2.59(m, 3H), 3.07-3.14 (ddd, J=13.60, 10.56, 3.23 Hz, 1 H) 3.70-3.80 (m, 2H) 4.37 (d, J=0.59 Hz, 1 H) 4.69 (d, J=10.76 Hz, 1 H) 5.14-5.23 (m, 2H)5.75-5.85 (m, J=17.17, 9.83, 7.43, 7.43 Hz, 1H) 6.68 (dt, J=7.38, 1.59Hz, 1H) 6.90-6.94 (m, 3H) 7.04 (m, 2H), 7.12 (d, J=8 Hz, 2H). MassSpectrum (ESI) m/z=486.3 (M+1)

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)aceticacid (Isomer 1)

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-2-one(major diastereomer; first eluting compound; Example 121, Step C) by aprocedure similar to the one described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.61 (t, J=7.63 Hz, 3 H) 1.34 (s, 3H) 1.46-1.56 (m, 2 H) 1.72 (s, br, 3 H) 1.82-1.89 (m, 2 H) 2.00-2.14 (m,2 H) 2.61 (d, J=13.89 Hz, 2 H) 2.76-2.84 (m, 2 H) 3.20 (dd, J=13.30,7.24 Hz, 2 H) 3.29 (br. s., 1 H) 3.73 (td, J=7.87, 5.18 Hz, 1 H) 4.34(d, J=10.37 Hz, 1 H) 6.68 (dd, J=7.43, 1.56 Hz, 1 H) 6.87 (s, 1 H)7.00-7.15 (m, 4 H) 7.14 (dd, J=8.12, 0.5 Hz, 2 H). Mass Spectrum (ESI)m/z=504.3 (M+1)

Example 2222-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-3-yl)aceticacid (Isomer 2)

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-1-(tetrahydrofuran-2-yl)propyl)piperidin-2-one(minor diastereomer; second eluting compound; Example 121, Step C) by aprocedure similar to the one described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.46 (t, J=7.63 Hz, 3 H) 1.15-1.26(m, 3 H) 1.36 (s, br. 3H), 1.46-1.50 (m, 1H), 1.79-1.85 (m, 4H),2.05-2.09 (dd, J=12, 4 Hz, 1H), 2.17 (t, J=12 Hz, 1H), 2.51 (s, br, 1H),2.66 (d, J=12 Hz, 1 H), 2.77 (d, J=12 Hz, 1 H), 3.76 (m, 2 H), 4.68 (d,J=8 nHz, 1H), 6.76 (d, J=8 Hz, 1H), 6.92-7.03 (m, 3H), 7.06 (d, J=2.2Hz, 2H), 7.16 (d, J=8.8 Hz, 2H). Mass Spectrum (ESI) m/z=504.3 (M+1)

Example 2232-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(5-oxotetrahydrofuran-2-yl)propyl)piperidin-3-yl)aceticacid

The title compound was prepared using the oxidation procedure of Example221, but using a larger excess of sodium periodate (7 eq) and reactingfor a longer period of time (18 h). ¹H NMR (400 MHz, CD₃OD) δ ppm 0.7(s, be, 3H), 1.42 (s, br, 3H), 1.68-1.75 (m, 1H), 1.96 (m, 1H),2.21-2.24 (m, 3H), 2.33 (m, 1H), 2.49-2.67 (m, 3H), 2.97 (d, J=12 Hz,1H), 3.37 (m, 2H), 3.51 (m, 1H), 4.60 (d, J=8 Hz, 1H), 6.96 (m, 1H),7.10 (s, 1H) 7.13-7.19 (m, 2H), 7.31 (s, br, 4H). Mass Spectrum (ESI)m/z=518.2 (M+1).

Example 2242-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)aceticacid (Isomer 1)

Step A.(3S,5R,6S)-3-Allyl-1-((3S)-8-((tert-butyldimethylsilyl)oxy)-4-hydroxyoctan-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

The title compound was prepared as a mixture of diastereomers by aprocedure similar to the one described in Example 221, Step A,substituting (4-chlorobutoxy)(tert-butyl)dimethylsilane for(3-bromopropoxy)(tert-butyl)dimethylsilane during the preparation of theGrignard reagent. Mass Spectrum (ESI) m/z=632.2 (M+1).

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4,8-dihydroxyoctan-3-yl)-3-methylpiperidin-2-one

The title compound was obtained from(3S,5R,6S)-3-allyl-1-((3S)-8-((tert-butyldimethylsilyl)oxy)-4-hydroxyoctan-3-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 224, Step B) by using a procedure similar to the one describedin Example 221, Step B. The diastereomer ratio was observed by NMR to beabout 2:1.

¹H NMR (400 MHz, d₄-methanol) representative signals:

major diastereomer δ ppm 0.45 (t, J=7.6 Hz, 3H), 4.76 (d, J=12 Hz, 1H).

minor diastereomer: δ ppm 0.54 (t, J=7.6 Hz, 3H), 4.53 (d, J=12 Hz, 1H).m/z=518.2 (M+1).

Step C.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one

A solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-4,8-dihydroxyoctan-3-yl)-3-methylpiperidin-2-one(31 mg, 0.060 mmol; diastereomeric mixture; Example 224, Step B) andtriphenylphosphine (31.4 mg, 0.12 mmol) in dichloromethane (1.5 mL) wastreated with (E)-diethyl diazene-1,2-dicarboxylate (0.02 ml, 0.12 mmol)at ambient temperature for 2 hours. Purification by silicachromatography eluting with ethyl acetate/hexane provided the titlecompound as a mixture of diastereomers.

¹H NMR (400 MHz, d4-Methanol) representative signals:

major diastereomer δ ppm 0.46 (t, J=8 Hz, 3H), 4.75 (d, J=12 Hz, 1H).

minor diastereomer δ ppm 0.55 (t, J=8 Hz, 3H), 4.53 (d, J=12 Hz, 1H).

Mass Spectrum (ESI) m/z=500.2 (M+1)

Step D.(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one

A solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one(3 mg, 5.99 μmol; Example 224, Step C) in THF (37.5 μL), H₂O (25 μL) andt-butanol (21 μL) was treated with 4-methylmorpholine N-oxide (2.45 mg,0.021 mmol) and 2.5% osmium tetroxide in t-BuOH (2 μL, 0.15 μmol) atambient temperature for 18 h. The mixture was diluted with ethylacetate, washed with water then sat. aq. NaCl solution and dried oversodium sulfate. After concentration the diastereomeric mixture was usedin the next step without further purification. Mass Spectrum (ESI)m/z=534.1 (M+1)

Step E.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetaldehyde

A solution of(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-2-one(3 mg, 5.61 μmol; Example 224, Step D) in water (20.0 μL) and THF (40.0μL) was treated with sodium periodate (3.60 mg, 0.02 mmol). After aprecipitate formed, methanol (40 μL) was added to form an emulsion whichwas stirred at ambient temperature for 1 hour. The reaction was dilutedwith sat. aq. NaCl solution and extracted with ethyl acetate. Thecombined organic layers were dried over sodium sulfate, filtered and thefiltrate was concentrated to provide a mixture of two diastereomerswhich was used in the next step. Mass Spectrum (ESI) m/z=502.1 (M+1)

Step F.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)aceticacid (Isomer 1)

A solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)acetaldehyde(3 mg, 5.97 μmol; mixture of stereoisomers, Example 224, Step E) in asolution of 1.25 M potassium phosphate monobasic in water (0.050 mL),t-butanol (0.050 mL) and 2.0 M 2-methylbut-2-ene in THF (0.15 mL, 0.30mmol) was treated with sodium chlorite (2.16 mg, 0.024 mmol) at ambienttemperature for 3 h. The reaction was quenched with 1 M sodiumthiosulphate solution (0.03 mL). After 10 min, the mixture was acidifiedwith 1M potassium bisulphate solution (0.03 mL) and extracted with ethylacetate. The organic layers were washed with sat. aq. NaCl solution anddried over anhydrous sodium sulfate. Purification by reversed phasepreparatory HPLC (eluent: 0 to 100% MeCN+0.1% TFA in water+0.1% TFA,over 20 minutes) gave the title compound as the first eluting isomer.

¹H NMR (400 MHz, MeOH-D4) δ ppm 0.51 (t, J=8 Hz, 3H), 1.03 (m, 1H), 1.32(s, br, 1H), 1.39 (s, 3H), 1.50 (m, 2H), 1.67 (m, 1H), 1.85 (m, 1H),1.96 (m, 3H), 2.19-2.22 (m, 2H), 2.60 (d, J=12 Hz, 1H), 2.99 (d, J=12Hz, 1H), 3.16 (m, 1H), 3.44 (m, 1H), 3.51 (m. 1H), 3.85 (m, 1H), 4.57(d, J=12 hZ, 1H), 6.97-6.99 (m, 1H), 7.06 (s, br, 1H), 7.15-7.21 (m,3H), 7.29-7.31 (d, J=8 Hz, 2H). Mass Spectrum (ESI) m/z=518.2 (M+1).

Further elution provided Example 225 as the second eluting isomer.

Example 2252-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((1S)-1-(tetrahydro-2H-pyran-2-yl)propyl)piperidin-3-yl)aceticacid (Isomer 2)

¹H NMR (400 MHz, MeOH-d4) δ ppm 0.39 (t, J=8 Hz, 3H), 1.00-1.07 (m, 1H),1.18-1.20 (m, 1H), 1.32 (s, br, 1H), 1.37 (s, br, 3H), 1.50-1.68 (m,4H), 1.86 (m, 2H), 2.15-2.19 (m, 2H), 2.58 (d, J=16 Hz, 1H), 2.96 (d,J=16 Hz, 1H), 3.41 (m, 1H), 3.52 (m, 1H), 3.89-3.94 (m, 1H), 4.11 (m,1H), 3.71 (d, J=8 HZ, 1H), 6.94 (m, 1H), 7.03 (s, br, 1H), 7.14-7.20 (m,4H), 7.28-7.30 (d, J=8 HZ, 2H). Mass Spectrum (ESI) m/z=518.2 (M+1)

Example 2262-((3R,5R,6S)-1-((R)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-1-((S)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Isomer 1)

Step A. 1-(Benzo[d]thiazol-2-yl)propan-1-ol

To a solution of 1,3-benzothiazole-2-carbaldehyde (0.96 g, 5.88 mmol) inTHF (15.0 mL) was added ethylmagnesium bromide (1.0 M solution in THF,12.0 mL, 12.0 mmol, 2 eq), slowly over 15 minutes (an exotherm wasobserved). The resulting dark red solution was stirred at roomtemperature for 55 minutes, then quenched with saturated aqueousammonium chloride solution (4 mL). The mixture was then concentratedunder reduced pressure. Purification by flash chromatography on silicagel (0-70% EtOAc in hexanes gradient) provided the title compound as ared oil.

Step B. 2-(1-Bromopropyl)benzo[d]thiazole

To a 0° C. solution of 891.4 mg (4.61 mmol) of1-(benzo[d]thiazol-2-yl)propan-1-ol (Example 1, Step A) in THF (12.0 mL)was added triphenylphosphine (1.8 g, 6.86 mmol, 1.5 eq), followed bycarbon tetrabromide (2.22 g, 6.69 mmol, 1.5 eq). The resulting mixturewas stirred at 0° C. for 35 minutes, then allowed to warm to roomtemperature overnight. The reaction mixture was then concentrated underreduced pressure. Purification by flash chromatography on silica gel(0-50% EtOAc in hexanes gradient) provided the title compound as a darkoil.

Step C.(3S,5R,6S)-3-Allyl-1-((R)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-Allyl-1-((S)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

To a suspension of sodium hydride (60% dispersion in oil, 100.0 mg,2.500 mmol, 3.1 eq) in DMF (1 mL) at 0° C. was added a solution of 300mg (0.801 mmol) of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) in DMF (1 mL) over 1 minute. After 5 minutes, asolution of 576.7 mg (2.25 mmol, 2.8 eq) of2-(1-bromopropyl)benzo[d]thiazol (Example 226, Step B) in DMF (1 mL) wasadded dropwise. The resulting mixture was allowed to warm to roomtemperature overnight. The reaction was quenched with water, and thenconcentrated under reduced pressure. Purification by reverse-phasepreparative HPLC (Agilent Eclipse Plus C18 column (Agilent Technologies,Santa Clara, Calif.), 0.1% TFA in CH₃CN/H₂O, gradient 70% to 90% over 25minutes) provided a mixture of the title compounds as a white solid.

Step D.2-((3R,5R,6S)-1-((R)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-1-((S)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Isomer 1)

To a solution of 97.5 mg (0.177 mmol) of(3S,5R,6S)-3-allyl-1-((R)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

(Example 226, Step C) in acetonitrile (1 mL), water (1.5 mL), and carbontetrachloride (1 mL) were added sodium periodate (154.2 mg, 0.721 mmol,4.1 eq), followed by ruthenium(III) chloride hydrate (11.0 mg, 0.049mmol, 0.27 eq). The resulting mixture was stirred at room temperaturefor 2.75 hours, then passed through a 0.45 μm filter to remove residualsolids, and then concentrated under reduced pressure. Purification byreverse-phase preparative HPLC (Agilent Eclipse Plus C18 column (AgilentTechnologies, Santa Clara, Calif.), 0.1% TFA in CH₃CN/H₂O, gradient 40%to 80% over 25 minutes) provided one of the title compounds as the firsteluting isomer as a white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.05 (t, J=7.46 Hz, 3 H) 1.55 (s, 3H) 2.10-2.32 (m, 3 H) 2.41-2.54 (m, 1 H) 2.87-2.98 (m, 2 H) 3.16-3.25(m, 1 H) 4.62 (d, J=10.27 Hz, 1 H) 4.81 (dd, J=8.56, 6.85 Hz, 1 H) 6.71(d, J=7.58 Hz, 1 H) 6.80 (d, J=8.07 Hz, 2 H) 6.88 (d, J=8.31 Hz, 2 H)6.96 (s, 1 H) 7.03-7.10 (m, 1 H) 7.16 (dd, J=7.95, 0.86 Hz, 1 H)7.42-7.47 (m, 1 H) 7.48-7.54 (m, 1 H) 7.85 (t, J=8.19 Hz, 2 H). MassSpectrum (ESI) m/z=567 (M+1).

Example 2272-((3R,5R,6S)-1-((R)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-1-((S)-1-(Benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Isomer 2)

One of the title compounds (Isomer 2) was prepared from(3S,5R,6S)-3-allyl-1-((S)-1-(benzo[d]thiazol-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 226, Step C) as the second eluting isomer as described inExample 226, Step D.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.77 (t, J=7.34 Hz, 3 H) 1.39 (s, 3H) 2.03-2.16 (m, 2 H) 2.16-2.24 (m, 1 H) 2.58 (dt, J=14.61, 7.49 Hz, 1H) 2.82-2.98 (m, 2 H) 3.20-3.29 (m, 1 H) 4.75-4.84 (m, 2 H) 6.75 (d,J=7.58 Hz, 1 H) 6.94 (s, 1 H) 7.00 (d, J=8.31 Hz, 2 H) 7.05-7.11 (m, 3H) 7.13-7.17 (m, 1 H) 7.44-7.49 (m, 1 H) 7.53 (t, J=7.46 Hz, 1 H) 7.87(d, J=8.07 Hz, 1 H) 8.01 (d, J=8.07 Hz, 1 H). Mass Spectrum (ESI)m/z=567 (M+1).

Examples 228 to 240 were also prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) as described in Example 226, substituting2-(1-bromopropyl)benzo[d]thiazole in Example 226, Step C, with anequivalent amount of the appropriate alkylhalide. The requiredalkylhalides (reagents) are prepared as described in the individualexamples.

Example R Reagent used 228

5-(1-Bromopropyl)-3- methylisoxazole 229

2-(1-Bromopropyl)-6- chloropyridine 230

2-(1-Bromopropyl) pyridine 231

2-(1-Bromobutyl) pyridine 232

2-(1-Bromo-2- cyclopropylethyl) pyridine 233

3-(1-Bromopropyl) pyridine 234

2-(1-Bromopropyl) pyrazine 235

2-(1-Bromopropyl) pyrimidine 236

2-(1-Bromopropyl)-6- methylpyridine 237

4-(1-Bromopropyl) pyridine 238

2-(1-Bromopropyl)-6- (trifluoromethyl)pyridine 239

2-(1-Bromopropyl)-6- bromopyridine 240

2-(1-Bromopropyl) thiazole

Example 2282-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(3-methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(3-methylisoxazol-5-yl)propyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.74 (t, J=7.43 Hz, 3 H) 1.33 (s, 3H) 1.90-2.11 (m, 2 H) 2.14-2.29 (m, 5 H) 2.90 (q, J=7.24 Hz, 2 H)3.37-3.47 (m, 1 H) 4.47 (t, J=7.14 Hz, 1 H) 4.60 (d, J=10.37 Hz, 1 H)5.70 (s, 1 H) 6.80 (dt, J=7.48, 1.54 Hz, 1 H) 6.90-7.02 (m, 3 H)7.04-7.19 (m, 4 H). Mass Spectrum (ESI) m/z=515 (M+1).

Synthesis of 5-(1-bromopropyl)-3-methylisoxazole

Step A. 1-(3-methylisoxazol-5-yl)propan-1-ol

To a solution of 3-methylisoxazole-5-carbaldehyde (0.801 g, 7.21 mmol)in 10 mL of THF at −78° C. was added ethylmagnesium bromide (3.60 mL,10.81 mmol) slowly. The reaction mixture was stirred at −78° C. for 2 h,then quenched with saturated aq. NH₄Cl solution, and extracted withether (3×80 mL). The combined organic layers were dried over Na₂SO₄filtered and the filtrate was evaporated to provide the crude product.The crude product was purified by chromatography on silica gel, elutingwith 10 to 60% EtOAc/hexane to provide the title compound. Mass Spectrum(ESI) m/z=142.2 (M+1).

Step B. 5-(1-Bromopropyl)-3-methylisoxazole

To a solution of 1-(3-methylisoxazol-5-yl)propan-1-ol (0.589 g, 4.17mmol) in 15 mL of THF was added CBr₄ (1.730 g, 5.22 mmol) andtriphenylphosphine (1.423 g, 5.42 mmol). The reaction mixture wasstirred at room temperature for 3 h. The solid was filtered off, andwashed with THF. The filtrate was concentrated and residue was purifiedby chromatography on silica gel, eluting with 5 to 30% EtOAc/hexane toprovide the title compound. Mass Spectrum (ESI) m/z=204.2 (M+1).

Example 2292-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-chloropyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-chloropyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.77 (t, J=7.43 Hz, 3 H) 1.30 (s, 3H) 1.99-2.13 (m, 2 H) 2.15-2.37 (m, 2 H) 2.70-2.90 (m, 2 H) 3.20 (ddd,J=12.96, 9.73, 3.33 Hz, 1 H) 4.56 (t, J=7.24 Hz, 1 H) 4.84 (d, J=9.98Hz, 1 H) 6.82 (dt, J=7.43, 1.56 Hz, 1 H) 6.88 (d, J=8.22 Hz, 2 H)6.99-7.24 (m, 7 H) 7.47 (t, J=7.73 Hz, 1 H). Mass Spectrum (ESI) m/z=545(M+1).

Synthesis of 2-(1-bromopropyl)-6-chloropyridine Step A.1-(6-Chloropyridin-2-yl)propan-1-ol

To a solution of 6-chloropicolinaldehyde (1.00 g, 7.06 mmol) in 20 mL ofTHF at −78° C. was added ethylmagnesium bromide, 3.0 M solution indiethyl ether (3.53 mL, 10.60 mmol) slowly. The reaction mixture wasstirred at −78° C. for 2 h. The reaction mixture was quenched with sat'dNH₄Cl aqueous solution, and extracted with ether (3×100 mL). Thecombined organic layers were dried over Na₂SO₄ and evaporated to providethe crude product. The crude product was purified by chromatography onsilica gel, eluting with 10 to 60% EtOAc/hexane to provide the titlecompound. Mass Spectrum (ESI) m/z=172 (M+1).

Step B. 2-(1-bromopropyl)-6-chloropyridine

A mixture of 1-(6-chloropyridin-2-yl)propan-1-ol (0.497 g, 2.90 mmol),CBr₄ (1.2 g, 3.62 mmol) and triphenylphosphine (0.987 g, 3.76 mmol) in25 mL of THF was stirred at room temperature for 2 h. The solid wasfiltered off and washed with THF. The filtrate was concentrated andresidue was purified by chromatography on silica gel, eluting with 10 to50% EtOAc/hexane to provide the title compound. Mass Spectrum (ESI)m/z=236 (M+1).

Example 2302-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridin-2-yl)propyl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyridin-2-yl)propyl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.75 (t, J=7.43 Hz, 3H), 1.21-1.31(m, 3H), 1.93-2.10 (m, 2H), 2.10-2.23 (m, 1H), 2.50 (dt, J=14.77, 7.48Hz, 1H), 2.75 (d, J=13.89 Hz, 1H), 2.97 (d, J=14.28 Hz, 1H), 3.09-3.25(m, 1H), 4.65 (dd, J=8.22, 6.06 Hz, 1H), 4.95 (d, J=9.00 Hz, 1H), 6.80(d, J=7.63 Hz, 1H), 6.89 (d, J=8.22 Hz, 2H), 7.02-7.21 (m, 6H), 7.34 (d,J=7.83 Hz, 1H), 7.54 (td, J=7.68, 1.66 Hz, 1H), 8.42 (d, J=4.30 Hz, 1H).Mass Spectrum (ESI)

m/z=511.1 (M+1).

Synthesis of 2-(1-bromopropyl)pyridine

To a mixture of 2-propylpyridine (2.5 g, 20.63 mmol, purchased fromSigma-Aldrich, St. Louis, Mo.) and(E)-2,2′-(diazene-1,2-diyl)bis(2-methylpropanenitrile) (1.253 g, 7.63mmol, purchased from Sigma-Aldrich) in CCl₄ (60 mL) at rt was addedn-bromosuccinimide (1.93 mL, 22.7 mmol, purchased from Sigma-Aldrich).The mixture was stirred under fluorescent light at rt for 12 hr. Theprecipitate was removed by filtration of the mixture through a pad ofCelite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth), which waswashed with CCl₄ (10 mL). The filtrate was concentrated under reducedpressure. Purification of the residue by flash chromatography on silicagel (eluent: 20% EtOAc/hexanes) provided the title compound as a yellowliquid. Mass Spectrum (ESI) m/z=199.9 and 201.9 (M+1).

Example 2312-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridin-2-yl)butyl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyridin-2-yl)butyl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.04 (m, 3H), 1.41-1.71 (m, 5H),2.03 (br. s., 1H), 2.18 (d, J=13.69 Hz, 1H), 2.30 (t, J=13.69 Hz, 1H),2.44-2.74 (m, 2H), 3.08 (d, J=15.26 Hz, 1H), 3.47 (t, J=10.56 Hz, 1H),4.31 (br. s., 1H), 4.59 (d, J=10.37 Hz, 1H), 6.77 (d, J=6.46 Hz, 1H),6.89-7.20 (m, 8H), 7.79 (br. s., 1H), 8.17 (br. s., 1H), 8.72-9.01 (m,1H), 11.51 (br. s., 1H). Mass Spectrum (ESI) m/z=525.1 (M+1).

Synthesis of 2-(1-bromobutyl)-6-chloropyridine Step A.1-(Pyridin-2-yl)butan-1-ol

To a solution of 2-bromopyridine (1.1 g, 6.96 mmol, purchased fromSigma-Aldrich) in diethyl ether (8 mL) at −78° C. under N₂ was addedbutyllithium (3.1 mL×2.5 M) over 10 min. The reaction solution wasstirred at −78° C. for 1.0 hr. To the mixture was added butyraldehyde(0.602 g, 8.35 mmol, purchased from Sigma-Aldrich) dropwise over 10 min.After stirring at −78° C. for 15 min, the mixture was allowed to warm tort and stirred at rt for 1.5 hr. The reaction mixture was poured intosaturated aqueous NH₄Cl solution (10 mL), diluted with water (15 mL),and extracted with EtOAc (20 mL×3). The organic layers were combined,washed with water, sat. aq. NaCl solution, and dried over MgSO₄. Afterremoval of organic solvents under reduced pressure, purification of theresidue by flash chromatography on silica gel with 20-80% EtOAc/Hexanesprovided the title compound as a white solid. Mass Spectrum (ESI)m/z=152.1 (M+1).

Step B. 2-(1-Bromobutyl)pyridine

To a mixture of 1-(pyridin-2-yl)butan-1-ol (0.35 g, 2.3 mmol; Example231, Step A) and triphenylphosphine (1.1 g, 4.2 mmol) in THF (15 mL) at0° C. under N₂ atmosphere was added CBr₄ (1.2 g, 3.5 mmol). The mixturewas stirred at 0° C. for 2 min, and then was allowed to warm to rt andstirred for 25 min. The precipitate was filtered off through a pad ofCelite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth), the solidwas washed with cold THF (10 mL). The filtrate was concentrated underreduced pressure. Purification of the residue by flash chromatography onsilica gel with 0-5-15% EtOAc/Hexanes provided the title compound ascolorless oil. Mass Spectrum (ESI) m/z=214.0 and 216.0 (M+1).

Example 2322-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-cyclopropyl-1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-2-cyclopropyl-1-(pyridin-2-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.45-−0.34 (m, 1H), −0.06 (dq,J=9.19, 4.63 Hz, 1H), 0.16-0.39 (m, 2H), 0.46 (dd, J=7.43, 5.28 Hz, 1H),1.16-1.31 (m, 3H), 1.63 (dt, J=13.60, 6.90 Hz, 1H), 2.00-2.17 (m, 2H),2.50-2.65 (m, 1H), 2.77 (br. s., 1H), 2.88 (d, J=9.59 Hz, 1H), 3.19 (t,J=8.80 Hz, 1H), 4.84 (br. s., 1H), 4.97 (d, J=9.19 Hz, 1H), 6.78 (d,J=7.43 Hz, 1H), 6.93 (d, J=7.83 Hz, 2H), 7.00-7.17 (m, 7H), 7.34 (d,J=7.43 Hz, 1H), 7.48-7.57 (m, 1H), 8.34-8.56 (m, 1H). Mass Spectrum(ESI) m/z=537.2 (M+1).

Synthesis of 2-(1-bromo-2-cyclopropylethyl)pyridine Step A.2-Cyclopropyl-1-(pyridin-2-yl)ethanol

To a solution of 2-cyclopropylacetaldehyde (1.00 g, 11.89 mmol,purchased from Beta Pharma, Inc., Branford, Conn.) in THF (15 mL) at 0°C. under N₂ was added 2-pyridylmagnesium bromide (47.6 mL×0.25 M,purchased from Rieke Metals, Inc., Lincoln, Nebr.) dropwise over 15 min.The mixture was stirred at 0° C. after 30 min, allowed to warm to rt andstirred at rt for 3.5 hr. To the reaction mixture was added saturatedaqueous NH₄Cl solution (5 mL) followed by water (15 mL). The mixture wasextracted with EtOAc (2×10 mL). The combined organic layers were driedover Na₂SO₄. After removal of organic solvents, purification of theresidue by flash chromatography on silica gel with 40-70% EtOAc/hexanesthe title compound was obtained as a white solid. Mass Spectrum (ESI)m/z=164.1 (M+1).

Step B. 2-(1-Bromo-2-cyclopropylethyl)pyridine

The title compound was prepared from2-cyclopropyl-1-(pyridin-2-yl)ethanol (Example 232, Step A) using aprocedure similar to the one described in Example 231, Step B. MassSpectrum (ESI) m/z=226.0 and 228.0 (M+1).

Example 2332-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridin-3-yl)propyl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyridin-3-yl)propyl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.97-1.10 (d, J=8.6 Hz, 3H), 1.44(s, 3H), 1.95-2.09 (m, 1H), 2.09-2.23 (m, 2H), 2.28 (s, 1H), 2.62 (d,J=13.89 Hz, 1H), 2.87 (d, J=13.89 Hz, 1H), 3.33 (ddd, J=13.40, 10.47,3.13 Hz, 1H), 4.37 (d, J=10.37 Hz, 1H), 5.93 (t, J=7.92 Hz, 1H),6.54-6.61 (m, 1H), 6.62-6.79 (m, 3H), 6.83-6.90 (m, 1H), 6.91-7.00 (m,1H), 7.00-7.07 (m, 1H), 7.07-7.15 (m, 1H), 7.15-7.23 (m, 1H), 7.26 (dd,J=8.02, 5.67 Hz, 1H), 7.36 (d, J=8.02 Hz, 1H), 8.35 (d, J=5.48 Hz, 1H),8.80 (s, 1 H). Mass Spectrum (ESI) m/z=511.1 (M+1).

Synthesis of 3-(1-bromopropyl)pyridine Step A.1-(Pyridin-3-yl)propan-1-ol

To a solution of 1-(pyridin-3-yl)propan-1-one (2.46 g, 18.20 mmol,purchased from Lancaster Synthesis Ltd.) in MeOH (15 mL) at rt under N₂atmosphere was added sodium borohydride powder (0.690 g, 18.20 mmol).After stirring at rt for 1.5 hr, to the reaction solution was addedwater (20 ml). The resulting mixture was stirred for 4 min, extractedwith EtOAc (20 mL×3). The organic layers were combined, washed withwater, sat. aq. NaCl solution and dried over MgSO₄. Removal of thesolvents provided the crude title compound as white solid. Mass Spectrum(ESI) m/z=138.0 (M+1).

Step B. 3-(1-Bromopropyl)pyridine

The title compound was prepared from 1-(pyridin-3-yl)propan-1-ol(Example 233, Step A) following the procedure described in Example 231,Step B. Mass Spectrum (ESI) m/z=199.9 and 201.9 (M+1).

Example 2342-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyrazin-2-yl)propyl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyrazin-2-yl)propyl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (t, J=7.14 Hz, 3H), 1.39 (s,3H), 1.94-2.24 (m, 4H), 2.71 (s, 2H), 3.39-3.54 (m, 1H), 4.46 (d, J=9.98Hz, 1H), 5.71 (t, J=7.43 Hz, 1H), 6.61 (d, J=7.82 Hz, 1H), 6.77 (br. s.,4H), 6.86-7.00 (m, 2H), 7.04 (d, J=8.80 Hz, 1H), 8.03-8.16 (m, 1H), 8.25(br. s., 1H), 8.34 (s, 1H). Mass Spectrum (ESI) m/z=512.1 (M+1).

Synthesis of 2-(1-bromopropyl)pyrazine

The title compound was prepared from 2-propylpyrazine (purchased fromMatrix Scientific) following a procedure similar to the one described inExample 230. Mass Spectrum (ESI) m/z=200.8 and 202.9 (M+1).

Example 2352-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyrimidin-2-yl)propyl)piperidin-3-yl)acetic

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.78 (t, J=7.43 Hz, 3H), 1.34 (s,3H), 1.90-2.07 (m, 1H), 2.08-2.19 (m, 1H), 2.20-2.34 (m, 1H), 2.52 (dt,J=14.33, 7.21 Hz, 1H), 2.80 (br. s., 1H), 2.93 (qd, J=7.27, 2.05 Hz,1H), 3.29-3.49 (m, 1H), 4.50 (br. s., 1H), 4.80 (d, J=10.17 Hz, 1H),6.79 (d, J=7.63 Hz, 1H), 6.90-7.19 (m, 8H), 8.60 (d, J=4.69 Hz, 2H).Mass Spectrum (ESI) m/z=512.2 (M+1).

Synthesis of 2-(1-bromopropyl)pyrimidine Step A. 2-Propylpyrimidine

To a 0° C. solution of triphenylphosphine (2.290 g, 8.73 mmol),nickel(II) acetylacetonate (0.464 mL, 2.62 mmol) and 2-chloropyrimidine(5.00 g, 43.7 mmol, purchased from Sigma-Aldrich) in THF (45 mL) underN₂ atmosphere was added propylmagnesium chloride (21.83 mL, 43.7 mmol)over 5 min. The mixture was allowed to warm to rt and stirred at rt for3 hr. To the reaction mixture was added saturated aqueous NH₄Cl solution(5 mL) followed by water (12 mL). The mixture was extracted with EtOAc(2×10 mL). The combined organic layers were dried over Na₂SO₄ filteredand concentrated. The residue was purified by flash chromatography onsilica gel (eluent: 0 to 50% EtOAc/hexanes) to provide the titlecompound as a colorless liquid.

Step B. 2-(1-Bromopropyl)pyrimidine

The title compound was prepared from 2-propylpyrimidine (Example 235,Step A) following a procedure similar to the one described in Example230. Mass Spectrum (ESI) m/z=201.0 and 203.0 (M+1).

Example 2362-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(6-methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-(6-methylpyridin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.99 (br. s., 3H), 1.39 (s, 3H),1.90-2.06 (m, 1H), 2.11 (d, J=12.72 Hz, 1H), 2.16-2.37 (m, 2H), 2.68 (d,J=15.06 Hz, 1H), 2.89 (s, 3H), 3.03 (d, J=15.06 Hz, 1H), 3.34 (t,J=10.76 Hz, 1H), 4.78 (d, J=9.59 Hz, 1H), 5.61 (br. s., 1H), 6.76 (d,J=7.04 Hz, 1H), 6.96 (br. s., 6H), 6.99-7.20 (m, 2H), 7.50 (d, J=7.43Hz, 1H), 7.90 (t, J=7.63 Hz, 1H), 8.60 (br. s., 1 H). Mass Spectrum(ESI) m/z=525.1 (M+1).

Synthesis of 2-(1-bromopropyl)-6-methylpyridine Step A.1-(6-Methylpyridin-2-yl)propan-1-ol

The title compound was prepared from 6-methyl-2-pyridinecarboxaldehyde(purchased from Tokyo Chemical Industry Co. Ltd.) using a proceduresimilar to the one described above for the synthesis of2-cyclopropyl-1-(pyridin-2-yl)ethanol (Example 232, Step A). MassSpectrum (ESI) m/z=151.4 (M+1).

Step B. 2-(1-Bromopropyl)-6-methylpyridine

The title compound was prepared from 1-(6-methylpyridin-2-yl)propan-1-ol(Example 236, Step A) following a procedure similar to the one describedin Example 231, Step B. Mass Spectrum (ESI) m/z=214.0 and 216.0 (M+1).

Example 2372-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(pyridin-4-yl)propyl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(pyridin-4-yl)propyl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.14 (t, J=7.14 Hz, 3H), 1.48-1.54(m, 3H), 1.94-2.09 (m, 1H), 2.09-2.32 (m, 2H), 2.64 (d, J=16.24 Hz, 1H),2.96-3.11 (m, 1H), 3.26 (d, J=16.24 Hz, 1H), 3.52-3.69 (m, 1H), 4.39 (d,J=10.37 Hz, 1H), 6.02 (br. s., 1H), 6.61 (d, J=7.63 Hz, 3H), 6.77 (br.s., 2H), 6.89-7.09 (m, 5H), 7.13 (d, J=7.43 Hz, 1H), 8.33 (br. s., 1H).Mass Spectrum (ESI) m/z=511.1 (M+1).

Synthesis of 4-(1-bromopropyl)pyridine Step A.1-(Pyridin-4-yl)propan-1-ol

The title compound was prepared from 1-(pyridin-4-yl)propan-1-one(purchased from Waterstone Technology) following a procedure similar tothe one described for the synthesis of 1-(pyridin-3-yl)propan-1-ol(Example 233, Step A). Mass Spectrum (ESI) m/z=138.0 (M+1).

Step B. 4-(1-Bromopropyl)pyridine

The title compound was prepared from 1-(pyridin-4-yl)propan-1-ol(Example 237, Step A) following a procedure similar to the one describedin Example 231, Step B. Mass Spectrum (ESI) m/z=199.9 and 201.9 (M+1).

Example 2382-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(6-(trifluoromethyl)pyridin-2-yl)propyl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.75 (t, J=7.43 Hz, 3H), 1.21-1.30(m, 3H), 1.98-2.19 (m, 2H), 2.29 (t, J=13.50 Hz, 1H), 2.47 (dt, J=14.62,7.46 Hz, 1H), 2.78 (d, J=14.87 Hz, 1H), 2.98 (d, J=14.87 Hz, 1H),3.14-3.28 (m, 1H), 4.23-4.33 (m, 1H), 5.05 (d, J=9.98 Hz, 1H), 6.84 (d,J=7.24 Hz, 1H), 6.91-7.06 (m, 3H), 7.10-7.22 (m, 4H), 7.54 (d, J=7.63Hz, 2H), 7.80 (t, J=7.83 Hz, 1H). Mass Spectrum (ESI) m/z=579.0 (M+1).

Synthesis of 2-(1-bromopropyl)-6-(trifluoromethyl)pyridine Step A.1-(6-(Trifluoromethyl)pyridin-2-yl)propan-1-ol

The title compound was prepared from 2-bromo-6-(trifluoromethyl)pyridine(purchased from Oakwood Products Inc., West Columbia, S.C.) andpropionaldehyde following the procedure as described above for thesynthesis of 1-(pyridin-2-yl)butan-1-ol (Example 231, Step A). MassSpectrum (ESI) m/z=206.1 (M+1).

Step B. 2-(1-Bromopropyl)-6-(trifluoromethyl)pyridine

The title compound was prepared from1-(6-(trifluoromethyl)pyridin-2-yl)propan-1-ol (Example 238, Step A)following a procedure similar to the one described for the synthesis of2-(1-bromobutyl)pyridine (Example 231, Step B). Mass Spectrum (ESI)m/z=268.0 (M+1) and 269.9 (M+1).

Example 2392-((3R,5R,6S)-1-((S)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-1-((R)-1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.66 (t, J=7.43 Hz, 3H), 1.23 (s,3H), 1.90-2.10 (m, 2H), 2.15-2.34 (m, 2H), 2.69-2.88 (m, 2H), 3.05-3.22(m, 1H), 4.29 (t, J=7.04 Hz, 1H), 4.84 (d, J=9.78 Hz, 1H), 6.77 (d,J=7.43 Hz, 1H), 6.85 (d, J=8.02 Hz, 2H), 6.97 (s, 1H), 6.99-7.14 (m,4H), 7.16-7.27 (m, 2H), 7.29-7.40 (m, 1H), 8.16 (br. s., 1H). MassSpectrum (ESI) m/z=589.0, 591.0, 593.0 (M+1).

Synthesis of 2-bromo-6-(1-bromopropyl)pyridine Step A.1-(6-Bromopyridin-2-yl)propan-1-ol

The title compound was prepared from 2,6-dibromopyridine (purchased fromSigma-Aldrich, St. Louis, Mo.) and propionaldehyde following a proceduresimilar to the one described above for the synthesis of1-(pyridin-2-yl)butan-1-ol (Example 231, step A). Mass Spectrum (ESI)m/z=219.9 and 217.9 (M+1).

Step B. 2-Bromo-6-(1-bromopropyl)pyridine

The title compound was prepared from 1-(6-bromopyridin-2-yl)propan-1-ol(example 239, Step A) following the procedure as described above for thesynthesis of 2-(1-bromobutyl)pyridine (Example 231, Step B). MassSpectrum (ESI) m/z=277.7, 279.7 and 281.7 (M+1).

Example 2402-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(thiazol-2-yl)propyl)piperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-1-(thiazol-2-yl)propyl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.66 (t, J=7.43 Hz, 3H), 1.19-1.41(m, 3H), 1.90-2.06 (m, 1H), 2.06-2.25 (m, 2H), 2.54 (dt, J=15.11, 7.60Hz, 1H), 2.77-2.98 (m, 2H), 3.14-3.37 (m, 1H), 4.57 (dd, J=8.41, 4.70Hz, 1H), 4.85 (d, J=9.78 Hz, 1H), 6.79 (d, J=7.43 Hz, 1H), 6.95 (s, 1H),6.99-7.24 (m, 6H), 7.40 (d, J=3.33 Hz, 1H), 7.83 (d, J=3.13 Hz, 1H),8.60 (br. s., 1H). Mass Spectrum (ESI) m/z=517.0 (M+1).

Synthesis of 2-(1-bromopropyl)thiazole

The title compound was prepared from 2-propylthiazole (purchased fromWaterstone Technologies, Inc., Carmel, Ind.) following a proceduresimilar to the one described above for the synthesis of2-(1-bromopropyl)pyridine (Example 230). Mass Spectrum (ESI) m/z=205.8and 207.8 (M+1).

Example 2412-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. Ethyl 6-propylpicolinate

A solution of ethyl 6-bromopicolinate (8 g, 34.8 mmol, purchased from AKScientific, Inc., Union City, Calif.) in THF (200 mL) was sparged withN₂ at 0° C. for 20 min. To the mixture under N₂ atmosphere was addedPd(PPh₃)₄ (3.21 g, 2.78 mmol) and a solution of propylzinc bromide (100mL, 0.5 M in THF, 50.0 mmol) dropwise over 30 min. The mixture wasremoved from the ice bath and heated to reflux for 18 h. After that timethe solution was cooled to rt, poured into saturated aqueous NH₄Clsolution (18 mL), diluted with water (30 mL), and extracted with EtOAc(3×30 mL). The combined organic layers were washed with water and sat.aq. NaCl solution and were dried over Na₂SO₄. After removal of theorganic solvents under reduced pressure, purification of the residue byflash chromatography on silica gel with 0 to 50% EtOAc/hexanes providedthe title compound. Mass Spectrum (ESI) m/z=194.0 (M+1).

Step B. Ethyl 6-(1-bromopropyl)picolinate

The title compound was prepared from Example 241, Step A following aprocedure similar to the one described for the synthesis of2-(1-bromopropyl)pyridine (Example 230). Mass Spectrum (ESI) m/z=272.0and 274.0 (M+1).

Step C. Ethyl6-((R)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)propyl)picolinateand ethyl6-((S)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)propyl)picolinate

The title compounds were prepared as a mixture from ethyl6-(1-bromopropyl)picolinate (Example 241, Step B) following a proceduresimilar to the one described in Example 226, Step C. Mass Spectrum (ESI)m/z=566.2 (M+1).

Step D.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methylpiperidin-2-one

To a 0° C. solution of ethyl6-((R)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)propyl)picolinateand ethyl6-((S)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)propyl)picolinate(160 mg, 0.283 mmol, Example 241, Step C) in THF (3 mL) under N₂ wasadded CH₃MgBr (3.0 M solution in diethyl ether, 0.377 mL, 1.132 mmol).The mixture was removed from the ice bath and stirred at rt for 30 min.To the reaction mixture was added additional CH₃MgBr (3.0 M solution indiethyl ether, 0.24 mL, 0.78 mmol). After stirring at rt for 2.0 hr, tothe reaction mixture was added saturated aqueous NH₄Cl solution (3 mL)and water (4 mL). The mixture was extracted with EtOAc (3×8 mL). Thecombined organic layers were washed with water, sat. aq. NaCl solution,and dried over Na₂SO₄. After removal of organic solvents under reducedpressure, purification of the residue by flash chromatography on silicagel with 20-80% EtOAc/hexanes provided the title compounds as a mixtureof stereoisomers. Mass Spectrum (ESI) m/z=551.1 (M+1).

Step E.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from a mixture of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-(2-hydroxypropan-2-yl)pyridin-2-yl)propyl)-3-methylpiperidin-2-one(Example 241, Step D) following a procedure similar to the one describedabove in example 230, Step C. Purification of the crude mixture asdescribed provided one of the title compounds as a single isomer as awhite solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.08-1.17 (m, 3H), 1.32-1.50 (m,9H), 1.87-1.97 (m, 1H), 1.97-2.08 (m, 1H), 2.08-2.18 (m, 1H), 2.27-2.48(m, 1H), 2.70 (br. s., 2H), 3.23 (br. s., 1H), 4.63-4.74 (m, 2H), 6.76(m, 3H), 6.84 (br. s., 1H), 6.93 (d, J=5.87 Hz, 2H), 6.99-7.11 (m, 3H),7.13-7.24 (m, 2H), 7.48 (br. s., 1H). Mass Spectrum (ESI) m/z=569.1(M+1).

Example 2422-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cyclopropylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-cyclopropylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cyclopropylpyridin-2-yl)propyl)-3-methylpiperidin-2-oneor(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-(6-cyclopropylpyridin-2-yl)propyl)-3-methylpiperidin-2-one

To a rt solution of mixture of((3S,5R,6S)-3-allyl-1-(1-(6-bromopyridin-2-yl)propyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(165 mg, 0.288 mmol; Example 239 in DMF (3 mL) was addedtricyclohexylphosphine (11.32 mg, 0.04 mmol), potassium phosphate (214mg, 1.009 mmol), cyclopropylboronic acid (49.5 mg, 0.577 mmol) anddiacetoxypalladium (4.53 mg, 0.020 mmol). The mixture was sparged withN₂ for 5 min and then heated to 80° C. for 5 hr. The resulting solutionwas cooled to rt, diluted with water (6 mL), and extracted with EtOAc (8mL×2). The organic layers were combined, washed with water, sat. aq.NaCl solution, and dried over MgSO₄. After removal of organic solventsunder reduced pressure, purification of the residue by flashchromatography on silica gel with 0 to 70% EtOAc/hexanes provided thetitle compound as a colorless syrup.

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(6-cyclopropylpyridin-2-yl)propyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(1-(6-cyclopropylpyridin-2-yl)propyl)-3-methylpiperidin-2-one(Example 242, Step A) following a procedure similar to the one describedin Example 71, Step F).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95-1.08 (m, 3H), 1.08-1.23 (m,2H), 1.36-1.44 (m, 3H), 1.44-1.54 (m, 1H), 1.54-1.66 (m, 1H), 1.99-2.29(m, 4H), 2.49-2.60 (m, 1H), 2.72 (d, J=15.26 Hz, 1H), 3.04 (d, J=15.26Hz, 1H), 3.30-3.43 (m, 1H), 4.71 (d, J=10.17 Hz, 1H), 5.52 (br. s., 1H),6.74 (d, J=7.63 Hz, 2H), 6.90-7.01 (m, 5H), 7.01-7.08 (m, 1H), 7.10 (d,J=8.02 Hz, 2H), 7.75 (t, J=8.02 Hz, 1H). Mass Spectrum (ESI) m/z=551.2(M+1).

Example 2432-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)aceticacid, 2,2,2-trifluoroacetic acid salt (1:1) or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((R)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)aceticacid, 2,2,2-trifluoroacetic acid salt (1:1)

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyridin-2-ylmethyl)piperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(2.246 g, 6 mmol; Example 71D) in DMF (25 mL) was added sodium hydride,60% dispersion in mineral oil (0.504 g, 12.60 mmol) and the mixture wasstirred at 0° C. for 5 minutes. To this was added2-(bromomethyl)pyridine hydrobromide (1.593 g, 6.30 mmol) at 0° C. Theresulting mixture was stirred at 0° C. for 10 min and quenched withsaturated NH₄Cl solution, extracted with EtOAc, washed with sat. aq.NaCl solution, dried over MgSO₄, filtered and the filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (eluent: 0 to 100% EtOAc in hexanes) to give the title compound.Mass Spectrum (ESI) m/z=465 (M+1).

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-2-oneor(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyridin-2-ylmethyl)piperidin-2-one(660 mg, 1.418 mmol; Example 243, Step A) in inhibitor free THF (7 mL)under N₂ at −78° C. was added lithium diisopropylamide (1.418 mL, 2.84mmol) and the mixture was stirred for 30 min.1,1,1-Trifluoro-2-iodoethane (744 mg, 3.55 mmol; Sigma, St. Louis, Mo.)was added and the orange reaction was stirred at −78° C. for 1 h. Thereaction was then warmed to rt and stirred overnight. The mixture wasquenched with 0.2 mL of MeOH, filtered, concentrated and the residue waspurified by HPLC (C18 column, eluted with 10-95% CH₃CN in Water, with0.1% TFA) to give the title compound as the slower eluting diasteromer.Mass Spectrum (ESI) m/z=547 (M+1).

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)aceticacid/2,2,2-Trifluoroacetic acid (1:1)

The title compound was obtained from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-2-one(61.2 mg, 0.112 mmol; Example 243, Step B) by a procedure similar to theone described in Example 71,

Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.96 (1 H, d, J=4.7 Hz), 8.09 (1 H,t, J=7.8 Hz), 7.86 (1 H, d, J=8.2 Hz), 7.56-7.68 (1 H, m), 7.22 (4 H,s), 7.08-7.17 (3 H, m), 6.94 (1 H, s), 6.90 (1 H, d, J=6.7 Hz),5.27-5.38 (1 H, m), 4.95 (1 H, d, J=6.5 Hz), 3.63 (1 H, dt, J=16.1, 9.8Hz), 3.28-3.40 (1 H, m), 2.88 (1 H, d, J=15.1 Hz), 2.74 (1 H, d, J=15.1Hz), 2.59-2.71 (1 H, m), 2.12-2.25 (1 H, m), 1.98-2.09 (1 H, m), 1.15 (3H, s). Mass Spectrum (ESI) m/z=565 (M+1).

Example 2442-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)aceticacid, as the 2,2,2-trifluoroacetic acid (1:1) salt

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-difluoro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pyridin-2-ylmethyl)piperidin-2-one(705 mg, 1.515 mmol; Example 71, Step D) in inhibitor free THF (7 mL)under N₂ at −78° C. was added lithium diisopropylamide (1.515 mL, 3.03mmol) and the mixture was stirred for 30 min. 1,1-Difluoro-2-iodoethane(727 mg, 3.79 mmol; Oakwood) was added and the orange reaction mixturewas stirred at −78° C. for 1 h. The reaction was warmed to rt overnightand quenched with 0.2 mL of MeOH, filtered and concentrated. The residuewas purified by HPLC (C18 column, eluted with 10-95% CH₃CN in water,with 0.1% TFA) to give(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-3,3-difluoro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one(HPLC retention time 7.38 min, Agilent Eclipse Plus C18 column, 0.1% TFAin CH₃CN/H₂O, gradient 70%-90% over 25 minutes) and(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-difluoro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one(HPLC retention time 7.94 min, Agilent Eclipse Plus C18 column (AgilentTechnologies, Santa Clara, Calif.), 0.1% TFA in CH₃CN/H₂O, gradient70%-90% over 25 minutes). Mass Spectrum (ESI) m/z=529 (M+1).

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-3,3,3-trifluoro-1-(pyridin-2-yl)propyl)piperidin-3-yl)aceticacid/2,2,2-Trifluoroacetic acid (1:1)

The title compound was obtained from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-difluoro-1-(pyridin-2-yl)propyl)-3-methylpiperidin-2-one(50 mg, 0.095 mmol; Example 244, Step A;) by a procedure similar to theone described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.03 (1 H, d, J=4.3 Hz), 8.17 (1 H,t, J=7.8 Hz), 7.79 (1 H, d, J=8.2 Hz), 7.72 (1 H, t, J=6.3 Hz),7.18-7.25 (4 H, m), 7.08-7.16 (2 H, m), 6.95 (1 H, s), 6.88-6.93 (1 H,m), 5.44 (1 H, br. s.), 5.31 (2 H, d, J=10.4 Hz), 5.21 (6 H, br. s.),5.10 (2 H, br. s.), 3.30-3.42 (1 H, m), 3.18 (1 H, br. s.), 2.90 (1 H,d, J=15.1 Hz), 2.72 (1 H, d, J=15.1 Hz), 2.44 (1 H, d, J=16.4 Hz), 2.27(1H, t, J=13.8 Hz), 1.98-2.08 (1 H, m), 1.21 (3 H, s). Mass Spectrum(ESI) m/z=547 (M+1).

Example 2452-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-methyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-2-methyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid

Step A: 2-(1-Bromo-2-methylpropyl)pyridine

The title compound was prepared from 2-isobutylpyridine (5.17 g, 38.2mmol; Alfa Aesar, Ward Hill, Mass.) following a procedure similar to theone described in Example 230. The reaction mixture was cooled to rt andfiltered, washing the filtered cake copiously with DCM. The filtrate wasconcentrated in vacuo and purified by chromatography on silica gel,eluting with a 0 to 25% gradient of EtOAc in hexanes. Fractionscontaining the desired product were concentrated to give the titlecompound.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-4S)-2-methyl-1-(pyridin-2-yl)propyl)piperidin-2-oneor(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-methyl-1-(pyridin-2-yl)propyl)piperidin-2-one

2-(1-Bromo-2-methylpropyl)pyridine (Example 245, Step A) and(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) were combined according to a procedure similar tothe one described in Example 226, Step C leading after separation to thetitle compound as the less abundant diastereomer. MS (ESI) 507 [M+H]⁺.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-methyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-2-methyl-1-(pyridin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained by treating the compound of Example 245,Step B by the procedure as described in Example 71, Step F.

¹H NMR (500 MHz, DICHLOROMETHANE-d₂) δ 0.87 (d, J=6.11 Hz, 3 H), 1.18(br. s., 3 H), 1.33-1.47 (m, 3 H), 1.96-2.10 (m, 1 H), 2.10-2.27 (m, 1H), 2.70-2.88 (m, 3 H), 3.19-3.30 (m, 1 H), 4.66 (d, J=9.54 Hz, 1 H),6.73 (d, J=7.58 Hz, 1 H), 6.84 (br. s., 2 H), 6.97 (br. s., 3 H),7.05-7.23 (m, 3 H), 7.55 (t, J=6.60 Hz, 1 H), 7.82 (t, J=8.31 Hz, 1 H),8.79 (d, J=4.89 Hz, 1 H). MS (ESI) 525 [M+H]⁺.

Example 246(3R,5R,6S)-3-((1H-tetrazol-5-yl)methyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one

The title compound was prepared from2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(pentan-3-yl)piperidin-3-yl)aceticacid (Example 71) as described in Example 86.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.49 (t, J=7.53 Hz, 3H) 0.97 (t,J=7.43 Hz, 3 H) 1.33 (s, 3 H) 1.37-1.58 (m, 2 H) 1.84-2.05 (m, 2 H)2.17-2.35 (m, 2 H) 2.77 (dt, J=9.00, 4.50 Hz, 1 H) 3.05-3.21 (m, 1 H)3.42-3.64 (m, 2 H) 4.36 (d, J=10.37 Hz, 1 H) 6.71 (d, J=7.63 Hz, 1 H)6.82 (d, J=7.63 Hz, 2 H) 6.98 (t, J=1.66 Hz, 1 H) 7.06-7.25 (m, 4 H).Mass spectrum (ESI) m/z 486.3 [M+H]⁺.

Example 247(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((R)-2,3-dihydroxypropyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-oneand(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((S)-2,3-dihydroxypropyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one

To a stirred solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one(185 mg, 0.40 mmol; Example 149, Step B) in THF (4 mL) under a nitrogenatmosphere at −8° C. (internal temperature) was added L-Selectride®(Aldrich, St. Louis, Mo.) (0.48 mL, 0.48 mmol, 1M solution in THF)dropwise over 2 minutes (internal temperature reached −5° C.). After 10minutes the reaction was quenched with MeOH (0.1 mL) and treated withOxone® (2 KHSO₅.KHSO₄. K₂SO₄, DuPont, Wilmington, Del.) (992 mg, 1.61mmol) in water (30 mL) and then it was stirred at rt for 2 hours. Afterthis time the reaction was partitioned between EtOAc (50 mL) and Na₂S₂O₃(30 mL, saturated aqueous solution). The separated organic layer waswashed with brine (20 mL) and then it was dried over MgSO₄, filtered andevaporated in vacuo to give the title compound. Mass Spectrum (ESI)m/z=460.0 (M+1).

Step B:(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-34R)-2,3-dihydroxypropyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-oneand(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((S)-2,3-dihydroxypropyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one

To a stirred solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one(75 mg, 0.163 mmol, Example 247, Step A) in t-BuOH (2 mL) was added4-methylmorpholine 4-oxide (76 mg, 0.652 mmol) and osmium tetroxide (2.1mg, 8.14 μmol) and the reaction was stirred at rt overnight. After thistime the reaction was partitioned between EtOAc (100 mL) and Na₂S₂O₃ (40mL, saturated aqueous solution). The separated organic layer was washedwith NaHCO₃ (40 mL, saturated aqueous solution), dried over MgSO₄,filtered and evaporated in vacuo. The resulting residue was purified byreverse phase HPLC (Sunfire™ Prep C₁₈ OBD 10 μm column (Waters, Milford,Mass.), gradient of elution of 20% MeCN in water to 80% MeCN in waterover a 30 min period, where both solvents contain 0.1% TFA) to give thetitle compounds as a separable mixture of diastereomers.

1^(st) eluted isomer: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.96-7.28 (8H, m), 6.73 (1 H, dt, J=7.6, 1.6 Hz), 4.39 (1 H, d, J=10.6 Hz),3.96-4.06 (1 H, m), 3.71 (1 H, dd, J=11.0, 3.5 Hz), 3.56 (1 H, dd,J=11.1, 7.3 Hz), 3.26-3.38 (1 H, m), 1.78-2.15 (6 H, m), 1.44 (3 H, s),1.19-1.39 (4 H, m), 0.50-0.67 (3 H, m). Mass Spectrum (ESI) m/z=494.0(M+1).

2^(nd) eluted isomer: ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 6.96-7.28 (8H, m), 6.70 (1 H, dd, J=6.2, 1.5 Hz), 4.38 (1 H, d, J=10.4 Hz), 4.31 (1H, br.s.), 3.66-3.76 (1H, m), 3.53-3.63 (1 H, m), 3.22-3.33 (1 H, m),1.80-2.32 (4 H, m), 1.45 (3 H, s), 1.16-1.45 (6H, m), 0.40-0.55 (3H,br.s.). Mass Spectrum (ESI) m/z=494.0 (M+1).

Example 2482-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylicacid

Step A. (3S,5R,6S)-Methyl1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carboxylate

A stirred solution of(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(1.3 g, 2.016 mmol; Example 185, Step D) in inhibitor free THF (10 mL)was degassed for 30 minutes with argon. The reaction was transferred viacannula over 5 minutes to a freshly prepared solution of LDA at −78° C.(the LDA solution was prepared by treating N,N-diisopropylamine (0.72mL, 5.04 mmol) in inhibitor free THF (2 mL) at −20° C. under an argonatmosphere with butyllithium (2.02 mL, 5.04 mmol, 2.5 M in hexanes) over1 minute and stirring the mixture at −15° C. for 30 minutes). Theresulting reaction mixture was stirred while warming to 0° C. over 30minutes. The reaction was cooled to −78° C. and treated with methylchloroformate (0.47 mL, 6.05 mmol) dropwise over 2 minutes. The reactionwas stirred at −78° C. for 2 hours and 30 minutes and then quenched with30 mL of a saturated aqueous NH₄Cl solution and allowed to warm to rt.The mixture was partitioned between ethyl acetate (150 mL) and water (50mL). The separated organic layer was dried over MgSO₄, filtered andevaporated in vacuo. Column chromatography (SiO₂, hexanes:EtOAc, 1:0 to4:1) gave the title compound. Mass Spectrum (ESI) m/z=702.1 (M+1).

Step B.(3R,5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-3-methylpiperidin-2-one

To a stirred solution of (3S,5R,6S)-methyl1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carboxylate(450 mg, 0.640 mmol; Example 248, Step A) at 0° C. in THF (4 mL) under anitrogen atmosphere was added dropwise lithium triethylborohydride (1.60mL, 1.60 mmol, 1M solution in THF). The reaction was stirred at 0° C.for 1 hour and then it was quenched with methanol (0.2 mL) and treatedwith Oxone® (2 KHSO₅.KHSO₄. K₂SO₄, DuPont, Wilmington, Del.) (1.18 g,1.92 mmol) in water (50 mL). The mixture was stirred for 1 hour and thenextracted with ethyl acetate (100 mL). The separated organic layer waswashed with Na₂S₂O₃ (50 mL, saturated aqueous solution) and then driedover MgSO₄, filtered and evaporated in vacuo. Column chromatography(SiO₂, hexanes:EtOAc, 1:0 to 7:3) gave the title compound. Mass Spectrum(ESI) m/z=674.2 (M+1).

Step C.(3R,5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carbaldehyde

To a stirred solution of(3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-3-methylpiperidin-2-one(210 mg, 0.311 mmol; Example 248, Step B) in CH₂Cl₂ (8 mL) at 0° C. wasadded NaHCO₃ (131 mg, 1.56 mmol) and Dess Martin periodinane (158 mg,0.373 mmol) in one portion. The reaction was stirred at rt for 2 hours.The reaction was diluted with CH₂Cl₂ (30 mL) and treated with Na₂S₂O₃(15 mL, saturated aqueous solution) and NaHCO₃ (15 mL, saturated aqueoussolution) at rt for 2 hours. The separated aqueous layer was extractedwith CH₂Cl₂ (2×50 mL) and the combined organic extracts were dried overMgSO₄, filtered and evaporated in vacuo to give the title compound. MassSpectrum (ESI) m/z=672.2 (M+1).

Step D. (E)-Methyl3-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate

To a stirred solution of THF (4 mL) and sodium hydride (16 mg, 0.40mmol, 60% dispersion in oil) under a nitrogen atmosphere at 0° C. wasadded trimethyl phosphonoacetate (61 μL, 0.43 mmol) dropwise over 30seconds. The mixture was allowed to warm to rt for 30 minutes. Asolution of(3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidine-3-carbaldehyde(205 mg, 0.305 mmol; Example 248, Step C) in THF (3 mL) was added. Theresulting mixture was stirred at rt for 2 hours. The reaction waspartitioned between EtOAc (80 mL) and water (40 mL). The separatedorganic layer was dried over MgSO₄, filtered and evaporated in vacuo.Column chromatography (SiO₂, hexanes:EtOAc, 1:0 to 8:2) gave the titlecompound. Mass Spectrum (ESI) m/z=728.2 (M+1).

Step E. Methyl2-((3R,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate

To a stirred solution of sodium hydride (12 mg, 0.30 mmol, 60%dispersion in oil) in THF (1.0 mL) under an argon atmosphere was addedtrimethylsulfoxonium iodide (72 mg, 0.33 mmol) portionwise over 1minute. The reaction was stirred at rt for 1 hour. A solution of(E)-methyl3-((3R,5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate(120 mg, 0.165 mmol; Example 248, Step D) in DMSO (1.0 mL) was addeddropwise over 1 minute. The reaction was stirred at rt overnight. Afterthis time more sulfur ylide was synthesized by suspendingtrimethylsulfoxonium iodide (140 mg) in DMSO (0.5 mL) under a nitrogenatmosphere and treating the mixture with NaH (24 mg, 60% dispersion inoil) and stirring for 30 minutes. The sulfur ylide was then added to thereaction and the mixture was stirred at rt for 16 hours After this timemore sulfur ylide was synthesized by suspending trimesulfoxonium iodide(140 mg) in DMSO (0.5 mL) under a nitrogen atmosphere and treating themixture with NaH (24 mg, 60% dispersion in oil) and stirring for 30minutes. The sulfur ylide was then added to the reaction and the mixturewas stirred at rt for 16 hours. The reaction was partitioned betweenethyl acetate (70 mL) and NH₄Cl (30 mL, saturated aqueous solution). Theseparated organic layer was dried over MgSO₄, filtered and evaporated invacuo. Purification by reverse phase HPLC (Sunfire Prep C₁₈ OBD 10 μmcolumn, gradient elution of 40% MeCN in water to 100% MeCN in water overa 40 min period, where both solvents contain 0.1% TFA) gave the titlecompound as the first eluting and major diastereomer. Stereochemistry atthe cyclopropane is a single but unassigned diastereomer. Mass Spectrum(ESI) m/z=742.2 (M+1).

Step F.2-((3R,5R,6S)-1-((S)-1-(tert-Butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylicacid

To a stirred solution of the ester from Example 248, Step E (10 mg,0.013 mmol) in THF (1.0 mL) was added sodium hydroxide (404 μL, 0.404mmol, 1M aqueous solution). The reaction was stirred at rt for 24 hours.After this time the reaction was partitioned between EtOAc (30 mL) and1.0 M HCl (5 mL). The separated organic layer was dried over MgSO₄,filtered and evaporated in vacuo to give the title compound as a singlediastereomer. Mass Spectrum (ESI) m/z=728.2 (M+1).

Step G.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylicacid

To a stirred solution of the acid from Example 248, Step F (10 mg, 0.014mmol) in THF (0.2 mL) was added TBAF (0.1 mL, 1.0 M solution in THF).After 30 minutes more TBAF (0.1 mL, 1.0 M solution in THF) was added andthe reaction was stirred at rt for 3 hours. After this time the reactionwas partitioned between EtOAc (30 mL) and 1M aqueous HCl (5 mL). Theseparated organic layer was dried over MgSO₄, filtered and evaporated invacuo. The resulting residue was purified by reverse phase HPLC (SunfirePrep C₁₈ OBD 10 μm column, gradient elution of 20% MeCN in water to 80%MeCN in water over a 30 min period, where both solvents contain 0.1%TFA) to give the title compound.

¹H NMR (400 MHz, CD₃OD) δ ppm 7.29-7.34 (2 H, m), 7.06-7.21 (5 H, m),6.87-6.98 (1 H, m), 4.70 (1 H, d, J=11.0 Hz), 4.06 (1 H, dd, J=11.1, 9.3Hz), 3.45-3.56 (2 H, m), 2.89 (1 H, dt, J=8.9, 4.5 Hz), 2.48 (1 H, t,J=13.5 Hz), 1.92-2.04 (1 H, m), 1.78-1.88 (1 H, m), 1.61-1.72 (1 H, m),1.43-1.53 (2 H, m), 1.22-1.36 (6 H, m), 0.41-0.52 (3 H, m). MassSpectrum (ESI) m/z=490.0 (M+1).

Example 249 2-((3R,5R,6S)-1-((S)-2-(tert-Butoxy)-1-cyclopropyl-2-oxoethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-3-yl)aceticacid

Step A. Ethyl 2-bromo-2-cyclopropylacetate

To a solution of 2-cyclopropylacetic acid (24.7 g, 247 mmol) inanhydrous DCE (250 mL) was added thionyl chloride (22 mL, 302 mmol)dropwise for 5 minutes at 25° C. After being refluxed for 2 h, thereaction was cooled to room temperature, N-bromosuccinimde (53.6 g, 301mmol) and hydrogen bromide (48% aqueous solution) (0.195 mL, 1.727 mmol)were added successively at 25° C. The resulted mixture was heated torefux for 96 h. After the reaction mixture was cooled to roomtemperature, absolute EtOH (200 mL) was added and the resulting darkbrown solution was stirred at room temperature for an hour. The reactionmixture was concentrated under reduced pressure (35° C., 4.0 kilopascal)and the residue was suspended in carbon tetrachloride (300 mL) andpassed through a glass filter. The filtrate was concentrated underreduced pressure (35° C., 4.0 kilopascal). Purification of the crudeproduct by chromatography (silica gel, 330 g×2, 5% ethyl acetate/hexane)and concentration of the desired combined fractions under reducedpressure (35° C., 4.0 kilopascal) provided the title compound as a paleyellow liquid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.20-4.32 (2 H, m), 3.59 (1 H, d,J=10.4 Hz), 1.53-1.66 (1 H, m), 1.29-1.36 (3 H, m), 0.76-0.93 (2 H, m),0.51-0.61 (1 H, m), 0.40-0.47 (1 H, m).

Step B. (S)-Ethyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate

To a solution of(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-piperidin-2-one (8.01g, 25 mmol; Example 1, Step E) in DMF (60 mL) was added 60% sodiumhydride in mineral oil (2.0 g, 50 mmol) at 0° C. and the mixture thusobtained was stirred at same temperature for 30 min. To the mixture wasadded ethyl 2-bromo-2-cyclopropylacetate (12.18 g, 50 mmol) in DMF (10mL) dropwise and the mixture was stirred at room temperature 2 h, thenthe reaction was quenched with sat. ammonium chloride solution anddiluted with ethyl acetate. The organic layer was washed with 10% aq.citric acid, 5% aq. NaHCO₃ solution, water, sat. aq. NaCl solution, thendried over MgSO₄. The solvent was evaporated under reduced pressure andthe residue was purified by chromatography on silica gel eluting with20% to 50% ethyl acetate in hexane to give the title compound as thefirst eluting diastereomer, a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.34 (m, 1H), 0.23 (m, 1H), 0.38(m, 1H), 0.62 (m, 1H), 1.26 (t, J=8 Hz, 3H), 1.39 (m, 1H), 2.13 (m, 2H),2.63 (m, 2H), 3.09 (m, 1H), 3.20 (d, J=12 Hz, 1H), 4.07 (m, 2H), 4.81(d, J=8 Hz, 1H), 6.90 (dt, J=7.1, 1.7 Hz, 1H), 7.11-7.19 (m, 5H), 7.28(m, 2H). Mass Spectrum (ESI) m/z=446.2 (M+1).

Step C. (S)-tert-Butyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate

To a solution of (S)-ethyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate(500 mg, 1.12 mmol) (Example 249, Step B) in THF/MeOH/H₂O (5/5/5, 15 mL)was added lithium hydroxide (1.68 mL, 3.36 mmol) at rt, and then thereaction was heated to 60° C. After being stirred at 60° C. for 1.5 h,the reaction was quenched with saturated aqueous NH₄Cl solution andextracted (2×DCM). The combined organic layers were washed (1×sat. aq.NaCl solution), dried over Na₂SO₄, filtered and the filtrate wasconcentrated and concentrated under reduced pressure.

The crude acid (450 mg, 1.076 mmol) synthesized above was dissolved inDCM (10 mL) and sulfuric acid (115 uL, 2.151 mmol) was added, followedby 2-methylprop-1-ene (1.207 g, 21.51 mmol) at −78° C. The reactionvessel was sealed and the mixture was slowly warmed to ambienttemperature. After being vigorously stirred for 4 days, the reaction wasquenched with sat. aqueous NH₄Cl solution and extracted with ethylacetate. The combined organic layers were washed with sat. aq. NaClsolution and dried over sodium sulfate, filtered and the filtrate wasconcentrated under reduced pressure. Purification of the residue byflash chromatography on silica gel (eluent: 40% EtOAc/hexanes) providedthe title compound.

Step D. (S)-tert-Butyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)-2-cyclopropylacetate

A solution of lithium bis(trimethylsilyl)amide (1M in THF, 0.165 mL,0.165 mmol) was added dropwise at −78° C. to a solution of(S)-tert-butyl2-(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate(Example 249, Step C, 71 mg, 0.15 mmol) and allyl bromide (15.54 uL,0.165 mmol) in 0.5 mL of THF. The reaction was allowed to warm toambient temperature. After stirring for 2 h, the reaction was quenchedwith sat. aqueous ammonium chloride solution and extracted with ethylacetate. The combined organic layers were washed with sat. aq. NaClsolution and dried over sodium sulfate, then filtered and the filtratewas concentrated under reduced pressure. Purification by flashchromatography on silica gel eluting with ethyl acetate/hexane providedthe title compound.

Step E.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-cyclopropylacetamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained from (S)-tert-butyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxopiperidin-1-yl)-2-cyclopropylacetate(Example 249, Step D) by the procedure of example 71, step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.08 (m, 1 H), 0.49 (m, 1 H), 0.58(m, 1 H), 0.66 (m, 1 H), 1.02 (m, 1 H), 1.44 (s, 9 H), 1.99 (m, 1 H),2.19 (m, 1 H), 2.58 (dd, J=16.0, 4.0 Hz, 1 H), 2.66 (m, 1 H), 2.93 (dd,J=12.0, 12.0 HZ, 1 H), 3.20 (s, 1 H), 3.34 (d, J=12 HZ, 1 H), 5.37 (s, 1H), 7.14 (m, 1 H), 7.25-7.33 (m, 3 H), 7.37-7.45 (m, 4 H). Mass Spectrum(ESI) m/z=532.2 (M+1).

Example 2502-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid

Step A. Ethyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetate

Coupling of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 71, Step D) and ethyl 2-bromo-2-cyclopropylacetate (Example249, Step A) using the procedure as described in Example 9, step Aafforded the title compound as a mixture of two diastereomers.

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-ethoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained from diastereomeric ethyl2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetate(Example 250, Step A) using the oxidation procedure described in Example71, Step F. Individual stereoisomers were separated by chiral HPLC(150×30 mm CHIRALPAK® IC column (CHIRAL TECHNOLOGIES, INC., WestChester, Pa., USA) with 20% IPA (0.1% DEA)/CO₂, 50 mL/min, on Thar 350SFC (Thar Technologies, Inc., Pittsburgh, Pa.)) to give the titlecompound as the faster eluting stereoisomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.49-−0.40 (m, 1 H) 0.12-0.21 (m,1 H) 0.36-0.46 (m, 1 H) 0.64 (m, 1 H) 1.28 (t, J=7.14 Hz, 3 H) 1.37 (s,3 H) 1.40-1.56 (m, 1 H) 2.14-2.27 (m, 2 H) 2.83 (d, J=14.48 Hz, 1 H)2.95 (d, J=14.48 Hz, 1 H) 3.02 (d, J=9.78 Hz, 1 H) 3.22-3.36 (m, 1 H)4.06-4.22 (m, 2 H) 4.75 (d, J=9.39 Hz, 1 H) 6.81 (m, 1 H) 7.00-7.21 (m,5 H) 7.21-7.35 (m, 2 H). Mass Spectrum (ESI) m/z=518.0 (M+1).

Example 2512-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)piperidin-2-one

A solution of lithium borohydride (2M in THF, 15.46 mL, 30.9 mmol) wasadded to a solution at 0° C. of (S)-ethyl2-((2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-6-oxopiperidin-1-yl)-2-cyclopropylacetate(Example 249, Step B, 2.3 g, 5.15 mmol) in ether (40 mL). After stirringat ambient temperature for 20 hours, the reaction was quenched withsaturated aq. NH₄Cl solution and extracted into EtOAc. The organic layerwas washed with sat. aq. NaCl solution, dried over sodium sulfate andconcentrated to give the title compound as a solid, which was usedwithout further purification.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.00 (m, 1H), 0.23 (m, 1H),0.48-0.57 (m, 2H), 0.85 (m, 1H), 1.99 (m, 1H), 2.07 (m, 1H), 2.61 (m,2H), 2.64 (m, 1H), 3.22 (dd, J=11.2, 9.8 Hz, 1H), 3.42 (td, J=10.1, 4.3Hz, 1H), 3.60 (m, 1H), 4.93 (d, J=6.5 Hz, 1H), 6.89 (m, 1H), 7.09 (m,4H), 7.18 (m, 2H), 7.27 (m, 1H). Mass Spectrum (ESI) m/z=404.0 (M+1).

Step B.(5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one

The product of example 251 step A was converted to the title compound bya procedure similar to the one described in example 185 step C.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.70 (m, 1H), −0.40 (m, 1H), 0.02(m, 1H), 0.13 (m, 1H), 0.91 (s, 9H), 1.09 (m, 1H), 1.92-1.91 (m, 2H),2.47-2.50 (m, 2H), 2.78 (s, br, 1H), 2.80 (m, 1H), 3.31 (m, 1H), 3.98(m, 1H), 4.62 (d, J=7.8 Hz, 1H), 6.60 (m, 1H), 6.82-6.91 (m, 4H),6.91-7.03 (m, 3H), 7.18-7.26 (6H), 7.37-7.45 (m, 4H). Mass Spectrum(ESI) m/z=642.3 (M+1).

Step C.(5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

(5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 251 Step B, 7.9 g, 12.29 mmol) was converted to the titlecompound, mixture of diastereomers by the method of Example 185, Step D.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.15 (m, 1H), 0.00 (m, 1H),0.41-0.52 (m, 2H), 1.26 (s, 9H), 1.41 (m, 1H), 1.62 (d, J=7.2 Hz, 3H),2.09 (m, 1H), 2.30 (m, 1H), 2.87 (m, 1H), 3.28 (m, 2H), 3.68 (m, 1H),4.23 (m, 1H), 5.11 (d, J=6.1 Hz, 1H), 7.16-7.34 (m, 4H), 7.37-7.46 (m,4H), 7.51-7.65 (m, 6H), 7.74-7.78 (m, 4H).

Step D.(5R,6S)-3-Allyl-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

(5R,6S)-1-((S)-2-(tert-Butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(5.02 g, 7.64 mmol, Example 251, Step C) was converted into the titlecompound by the procedure described for Example 185, Step E. Afterworkup, the unpurified product was used as obtained.

Step E.2-((3R,5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

(5R,6S)-3-allyl-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 251, Step D, 106 mg, 0.15 mmol) was treated according to theprocedure of Example 185, Step F to provide2-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid. Mass Spectrum (ESI) m/z=714.3 (M+1).

Step F.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

A solution of tetrabutylammonium fluoride, (1.0 M in THF, 0.453 mL,0.453 mmol) was added to a solution of2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 251, Step E, 108 mg, 0.151 mmol) in THF (4 ml) and thereaction was stirred at ambient temperature for 20 hours. Analysis byLC-MS showed incomplete reaction so an extra 0.225 ml oftetrabutylammonium fluoride solution was added and the reaction wasstirred for another 26 hours. The mixture was diluted in ethyl acetatethen washed with water and sat. aq. NaCl solution. The organic layer wasdried over sodium sulfate and concentrated. Purification by RP-HPLC(Sunfire Prep C₁₈ OBD 10 μm column, gradient elution of 10% MeCN inwater to 80% MeCN in water over a 30 min period, where both solventscontain 0.1% TFA) afforded the title compound as a solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.30 (s, m, 1H), 0.00 (s, m, 1H),0.37 (m, 2H), 0.79 (m, 1H), 1.22 (s, 3H), 2.00 (m, 2H), 2.52 (d, J=14.1Hz, 1H), 2.70 (d, J=13.9 Hz, 1H), 3.00 (m, 2H), 3.20 (s, br, 3H), 3.29(m, 1H), 4.65 (d, J=10.0 Hz, 1H), 6.61 (m, 1H), 6.84 (s, br, 2H), 6.97(m, 3H), 7.04 (m, 2H). Mass Spectrum (ESI) m/z=476.2 (M+1).

Example 2522-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one

A solution of tetrabutylammonium fluoride in THF (1M, 2.10 mL, 2.10mmol) was added to a solution of diastereomers(5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 251, Step D, 488 mg, 0.700 mmol) in THF (10 ml).The reactionwas stirred at ambient temperature for 2 hours. The mixture was dilutedin ethyl acetate and washed with water and sat. aq. NaCl solution. Theorganic layer was dried over sodium sulfate. Silica gel chromatographyeluting with ethyl acetate/hexane gave the title compound as a singlediastereomer.

Mass Spectrum (ESI) m/z=458.0 (M+1)

Step B.(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 252, Step A, 80 mg, 0.17 mmol) was converted to the titlecompound as a white foam by the procedure described in Example 91, StepC. Mass Spectrum (ESI) m/z=456.1 (M+1)

Step C.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxybutyl)-3-methylpiperidin-2-oneor(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxybutyl)-3-methylpiperidin-2-one

By the procedure of Example 149, Step A, substituting ethyl magnesiumbromide for methyl magnesium bromide,(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde(Example 252, Step B, 90 mg, 0.20 mmol) was converted to the titlecompound which was obtained as the second eluting diastereomer afterchromatography.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.43 (m, 1H), −0.16 (m, 1H), 0.32(m, 1H), 0.51 (m, 1H), 0.78 (t, J=0.3 Hz, 3H), 1.18 (s, 3H), 1.21-1.35(m, 1H), 2.54 (m, 2H), 1.57 (s, br, 1H), 1.87-2.0 (m, 2H), 2.21 (s, br,1H), 2.50-2.62 (m, 2H), 3.22 (ddd, J=12.8, 10.2, 4.0 Hz, 1H), 3.68 (s,br, 1H), 4.34 (d, J=10.0 Hz, 1H), 5.12 (s, 1H), 5.14 (d, J=8 Hz, 1H),5.79 (m, 1H), 6.65 (dt, J=7.6, 1.6 Hz, 1H), 6.87-6.91 (m, 3H), 7.01-7.07(m, 2H), 7.16-7.18 (m, 2H). Mass Spectrum (ESI) m/z=486.3 (M+1)

Step D.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxybutyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained by treating the compound of Example 252,Step C by the method described in Example 71, Step F.

¹H NMR (400 MHz, Methanol-d4) δ ppm −0.16 (s, br, 1H), 0.26 (s, br, 1H),0.55 (s, br, 1H), 0.67 (s, br, 1H), 0.86 (m, 3H), 1.32 (m, 4H), 1.41 (s,3H), 1.68 (m, 1H), 1.92 (m, 2H), 2.64 (d, J=12 Hz, 1H), 2.99 (d, J=12Hz, 1H), 3.51 (m, 1H), 4.97 (m, 1H), 6.97 (m, 1H), 7.06 (m, 1H), 7.17(m, 4H), 7.28 (m, 2H). Mass Spectrum (ESI) m/z=504.1 (M+1).

Example 2532-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one

Using the procedure described for Example 185, Step D, substitutingethyl iodide for methyl iodide,(5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 251, Step B, 2.6 g, 4.05 mmol) was converted to the titlecompound as a foam.

¹H NMR (400 MHz, Methanol-d4) δ ppm −0.39 (m, 1H), −0.22 (m, 1H),0.20-0.24 (m, 1H), 0.35-0.38 (m, 1H), 1.03-1.19 (m, 14), 1.26 (t, J=4Hz,1H), 1.78-1.84 (m, 1H), 1.94-1.99 (m, 1H), 2.13-2.19 (m, 2H), 2.46-2.51(m, 1H), 3.24-3.26 (m, 1H), 3.52-3.53 (m, 1H), 5.0 (d, J=8 Hz, 1H), 7.06(m, 1H), 7.17-7.24 (m, 5H), 7.30-7.32 (m, 2H), 7.37-7.50 (m, 6H),7.58-7.62 (m, 4H). Mass Spectrum (ESI) m/z=670.2 (M+1)

Step B.(5R,6S)-3-Allyl-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethylpiperidin-2-one

Using the procedure described for Example 185, Step E,(5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 253, Step A, 1.6 g, 2.38 mmol) was converted to the titlecompound which was used without further purification.

Step C.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one

The title compound was prepared using a similar procedure as Example202, Step A. It was isolated as the second eluting diastereomer aftersilica gel chromatography eluting with ethyl acetate/hexanes.

¹H NMR (400 MHz, Methanol-d4) δ ppm −0.48 (m, 1H), −0.01 (m, 1H), 0.40(m, 1H), 0.48 (m, 1H), 0.97-1.01 (m, 3H), 1.37 (m, 1H), 1.49-1.58 (m,1H), 1.75-1.78 (d, J=12 Hz, 1H), 1.97 (m, 1H), 2.38 (t, J=16 Hz, 1H),2.65 (m, 2H), 2.76 (m, 1H), 3.94 (t, J=12 Hz, 1H), 4.79 (d, J=12 Hz,1H), 5.20-5.28 (m, 2H), 5.94-6.03 (m, 1H), 6.96 (s, br, 1H), 7.09 (s,2H), 3.01 (s, br, 3H), 7.29 (s, br, 2H). Mass Spectrum (ESI) m/z=472.1(M+1).

Step D.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonamide

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one(Example 253, Step C, 125 mg, 0.265 mmol) was converted to the titlecompound by the procedure described in Example 202, Step C.

¹H NMR (400 MHz, Methanol-d4) δ ppm −0.46 (s, br, 1H), −0.24 (s, br,1H), 0.48 (s, br, 2H), 0.96 (t, J=7.5 Hz, 3H), 0.99 (m, 6H), 1.71-1.79(m, 2H), 1.88 (m, 1H), 2.35 (t, J=16 Hz, 1H), 2.51 (s, br, 1H), 2.69 (m,2H), 3.43 (m, 2H), 4.89 (m, 1H), 5.17-5.28 (m, 2H), 5.94-6.05 (m, 1H),7.0 (m, 1H), 7.05 (m, 1H), 7.17-7.19 (m, 4H), 7.30 (m, 2H). MassSpectrum (ESI) m/z=589.2 (M+1).

Step E.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylcyclopropane sulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)acetic acid

The title compound was obtained fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonamide(Example 253, Step D) by the procedure described in Example 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.71 (s, br, 1H), −0.29 (s, br,1H), 0.31-0.41 (d, br, 2H), 0.88 (m, 6H), 1.10 (s, br, 2H), 1.19 (m,2H), 1.82-1.87 (m, 2H), 2.20-2.27 (m, 2H), 2.69-2.73 (d, J=16 Hz, 1H),2.82 (s, br, 4H), 2.97-3.03 (m, 3H), 4.72 (d, J=12 Hz, 1H), 6.77 (m,1H), 6.88 (s, br, 2H), 7.06 (m, 3H), 7.16 (s, br, 2H). Mass Spectrum(ESI) m/z=607.2 (M+1).

Example 2542-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one(Example 253, Step C,) was coupled with cyclopropanesulfonamide by theprocedure described in example 202, step C to afford the title compoundas a white foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.28 (s, br, 1H), 0.00 (s, br,1H), 0.36 (d, br, 2H), 0.66 (m, 7H), 0.89 (m, 2H), 1.50 (m, 1H), 1.53(dd, J=13.7, 3.1 Hz, 1H), 1.98 (t, J=13.7 Hz, 1H), 2.15 (m, 1H), 2.35(m, 1H), 2.44 (m, 1H), 2.71 (s, br, 1H), 2.85 (m, 1H), 2.97 (ddd,J=13.6, 10.6, 3.0 Hz, 1H), 3.13 (s, br, 1H), 4.54 (d, J=10.4 Hz, 1H),4.91-4.96 (m, 2H), 5.63-5.73 (m, 1H), 6.49 (dt, J=7.5, 1.5 Hz, 1H), 6.72(t, J=1.9 Hz, 2H), 6.85-6.91 (m, 3H), 6.94 (s, br, 2H). Mass Spectrum(ESI) m/z=575.2 (M+1).

Step B.N-((2S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide

A solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide(Example 254, Step A, 80 mg, 0.139 mmol) in THF (375 μL), water (250 μL)and t-butanol (208 μL) was treated with 4-methylmorpholine N-oxide (57.0mg, 0.486 mmol) followed by 2.5% osmium tetroxide in t-butanol (45.6 μL,3.47 μmol). After stirring at ambient temperature for 16 h, the mixturewas diluted with ethyl acetate and washed with water and sat. aq. NaClsolution. The organic layer was dried over sodium sulfate andconcentrated to provide the title compound as a mixture of diastereomers(85 mg) which was used directly in the next step. Mass Spectrum (ESI)m/z=609.1 (M+1)

Step C.N—((S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide

Sodium periodate (89 mg, 0.418 mmol) was added to a clear solution ofN-((2S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide(Example 254, Step B, 85 mg, 0.14 mmol) in water (0.5 mL) and THF (1mL). After several minutes, a solid formed. Methanol (1 ml) was addedand the resulting emulsion was stirred for 30 min. The reaction wasdiluted with sat. aq. NaCl solution and extracted twice with ethylacetate. The combined organic layers were washed with sat. aq. NaClsolution, dried over sodium sulfate and concentrated under the reducedpressure to provide the title compound (94 mg) which was used withoutpurification in the next step. Mass Spectrum (ESI) m/z=577.0 (M+1)

Step D.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

A solution of sodium chlorite (58.9 mg, 0.651 mmol) in 0.25×1.25 Mpotassium phosphate monobasic in water (1 mL) at 0° C. was added to aclear solution ofN—((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)cyclopropanesulfonamide(Example 254, Step C, 94 mg, 0.163 mmol) in 1.25 M potassium phosphatemonobasic in water (1 mL)+t-butanol (1 mL)+2 M 2-methylbut-2-ene in THF(4.07 mL, 8.14 mmol). After stirring at ambient temperature for 4 hours,the reaction was quenched with 0.6 mL of 1 M sodium thiosulfatesolution. After stirring for 10 min at ambient temperature, the mixturewas acidified with 1.2 mL of 1 M potassium bisulphate solution. Themixture was extracted with ethyl acetate. The organic layer was washedwith water then sat. aq. NaCl solution and dried over sodium sulfate.Purification by reverse phase HPLC (Sunfire Prep C₁₈ OBD 10 μm column,gradient elution of 20% MeCN in water to 80% MeCN in water over a 30 minperiod, where both solvents contain 0.1% TFA) afforded the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.00 (s, br, 1H), 0.30 (s, br, 1H),0.64 (d, br, 2H), 0.96 (m, 7H), 1.12 (m, 3H), 1.75-1.82 (m, 1H), 1.92(dd, J=13.8, 3.03 Hz, 1H), 2.02 (m, 1H), 2.34 (t, J=13.8 Hz, 1H), 2.47(m, 1H), 2.84 (s, br, 3H), 3.05 (dd, J=13.0, 5.18 Hz, 1H), 3.24 (ddd,J=13.5, 10.3, 2.74 Hz, 1H), 3.53 (s, br, 1H), 4.84 (d, J=10.4 Hz, 1H),6.78 (dt, J=7.63, 1.37 Hz, 1 H) 7.02 (t, J=1.86 Hz, 2 H) 7.10-7.20 (m, 5H). Mass Spectrum (ESI) m/z=593.0 (M+1).

Example 2552-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)ethanesulfonamide

Coupling of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one(Example 253, Step C) with ethylsulfonamide according to the procedureof Example 202, Step D afforded the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.29 (s, br, 1H), 0.00 (s, br,1H), 0.37 (d, br, 2H), 0.69 (t, J=7.3 Hz, 3H), 1.14 (t, J=8 Hz, 3H),1.30 (m, 1H), 1.56 (dd, J=13.7, 3.1 Hz, 1H), 1.69 (m, 1H), 2.01 (t,J=13.7 Hz, 1H), 2.38-2.40 (m, 1H), 2.44-2.48 (m, 1H), 2.77 (m, 4H),2.99-3.12 (m, 2H), 4.58 (d, J=10.6 Hz, 1H), 4.96 (s, 1H), 4.98 (dd,J=7.0, 2.0 Hz, 1H), 5.43 (s, br, 1H), 5.67-5.76 (m, 1H), 6.54 (dt,J=7.4, 1.6 Hz, 1H), 6.75 (s, br, 2H), 63.87-6.93 (m, 3H), 6.94 (s, br,2H). Mass Spectrum (ESI) m/z=563.2 (M+1).

Step B.N-((2S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)ethanesulfonamide

The title compound was prepared as a mixture of diastereomers using aprocedure similar to the one described in Example 254, Step B.

Step C.N—((S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxo-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)ethanesulfonamide

The title compound was prepared using a similar procedure as describedfor Example 254, Step C. Mass Spectrum (ESI) m/z=565.2 (M+1).

Step D.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained using a similar procedure as describedfor Example 254, step D.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.51 (s, br, 1H), 0.00 (s, br,1H), 0.39 (s, br, 1H), 0.47 (s, br, 1H), 0.97 (t, J=7.4 Hz, 4H), 1.32(t, J=7.4 Hz, 5H), 1.74-1.81 (m, 1H), 1.93-2.02 (m, 2H), 2.37 (t, J=12Hz, 1H), 2.64 (d, J=13.7 Hz, 1H), 2.91 (d, J=13.5 Hz, 1H), 3.04 (m, 3H),3.40 (m, 1H), 4.90 (d, J=10.8 Hz, 1H), 6.99 (m, 1H), 7.05 (m, 2H),7.14-7.19 (m, 5H). Mass Spectrum (ESI) m/z=581.2 (M+1).

Example 2562-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylcyclopropane sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetic acid

Step A.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonamide

The title compound was prepared using a similar procedure as describedfor Example 202, Step D.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.71 (s, br, 1H), −0.31 (s, br,1H), 0.31 (s, br, 1H), 0.40 (s, br, 1H), 1.01 (m, 2H), 1.25 (m, 3H),1.29 (s, 3H), 1.59 (s, br, 1H), 1.85-1.89 (dd, J=13.6, 3.4 Hz, 2H), 2.22(m, 1H), 2.35 (s, br, 1H), 2.67 (d, J=8 Hz, 2H), 2.94 (s, 3H), 3.11 (m,1H), 3.19 (m, 1H), 4.78 (d, J=8 Hz, 1H), 5.19 (m, 2H), 5.25 (s, 1H),5.85-5.95 (m, 1H), 6.93 (m, 2H), 7.06 (m, 2H), 7.14 (m, 2H), 7.23 (m,2H). Mass Spectrum (ESI) m/z=575.2 (M+1).

Step B.N-((2S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2,3-dihydroxypropyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonamide

The title compound was prepared as a mixture of diastereomers using asimilar procedure to the one described in Example 254, Step B. MassSpectrum (ESI) m/z=609.1 (M+1).

Step C.N—((S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-3-(2-oxoethyl)piperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonamide

The title compound was prepared using a similar procedure as describedfor Example 254, Step C. Mass Spectrum (ESI) m/z=577.2 (M+1).

Step D.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared using a similar procedure as describedfor Example 254, Step D.

¹H NMR (400 MHz, Methanol-d4) δ ppm −0.71 (s, br, 1H), −0.28 (s, br,1H), 0.29 (s, br, 1H), 0.40 (s, br, 1H), 1.06 (d, br, 4H), 1.44 (s, 3H),1.73 (s, br, 1H), 2.08 (m, 1H), 2.20 (s, br, 1H), 2.35 (t, J=8 Hz, 1H),2.57 (s, br, 1H), 2.70 (d, J=12 Hz, 1H), 2.94 (s, 3H), 2.99 (d, J=12 Hz,1H), 3.07 (m, 1H), 3.42 (m, 1H), 4.40 (s, br, 1H), 4.82 (d, J=8 Hz, 1H),7.02-7.05 (m, 3H), 7.11 (m, 3H), 7.31 (s, br, 2H). Mass Spectrum (ESI)m/z=593.2 (M+1).

Example 2572-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

The mixture of diastereomers prepared from(5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(4.34 g, 6.61 mmol) by the method of Example 251, Step D was purified bysilica gel chromatography, eluting with ethyl acetate/hexanes. Fractionscontaining the desired epimer were combined and concentrated to give(3S,5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-oneas a white foam weighing 3.01 g (65% yield). MS (ESI) m/z=696 [M+H]⁺.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one.(see also Example 252 step A)

Treating(3S,5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 257, Step A, 3.00 g, 4.31 mmol) according to the procedure ofExample 252, Step A gave(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-oneas a white foam (1.905 g, 97%).

¹H NMR (500 MHz, CHLOROFORM-d) δ 0.00-0.15 (m, 1 H), 0.18-0.35 (m, 1 H),0.44-0.69 (m, 2 H), 0.75-0.87 (m, 1 H), 1.28 (s, 3 H), 1.87-2.03 (m, 2H), 2.48-2.72 (m, 2 H), 3.01-3.22 (m, 2 H), 3.41 (td, J=10.33, 4.52 Hz,1 H), 3.60 (dd, J=11.00, 4.40 Hz, 1 H), 4.86 (d, J=10.03 Hz, 1 H),5.06-5.24 (m, 2 H), 5.74-5.97 (m, 1 H), 6.74 (d, J=7.58 Hz, 1 H),6.86-7.10 (m, 3 H), 7.10-7.26 (m, 4 H). MS (ESI) m/z=458 [M+H]⁺

Step C.(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde.(see also Example 252 step B)

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 257, Step B, 1.01 g, 2.2 mmol) was converted to the titlecompound as a white foam (866 mg, 86%) by the procedure described in

Example 91, Step C. MS (ESI) m/z=456 [M+H]⁺.

Step D.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one

By the procedure of Example 149, Step A,(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde(Example 257, Step C, 866 mg, 1.897 mmol) was treated with methylmagnesium bromide to give the diastereomeric alcohols(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-oneas a white foam. MS (ESI) m/z=472 [M+H]⁺.

Step E.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxypropyl)-3-methylpiperidin-2-one(Example 257, Step D, 809 mg, 1.71 mmol) was treated according to theprocedure described in Example 71, Step F, to afford, after SFCpurification,2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid as a white solid.

¹H NMR (500 MHz, Methanol-D4) δ −0.70-−0.47 (m, 1 H), 0.10 (dq, J=9.78,5.05 Hz, 1 H), 0.31-0.48 (m, 1 H), 0.63 (tt, J=8.59, 5.35 Hz, 1 H), 1.34(s, 3 H), 1.47-1.58 (m, 1 H), 2.15-2.35 (m, 6 H), 2.65 (d, J=13.69 Hz, 1H), 2.79 (d, J=10.03 Hz, 1 H), 2.98 (d, J=13.69 Hz, 1 H), 3.48-3.57 (m,1 H), 4.65 (d, J=10.51 Hz, 1 H), 6.94-7.01 (m, 1 H), 7.08 (s, 1 H),7.11-7.54 (m, 6 H). MS (ESI) m/z=488 [M+H]⁺.

Step F.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2R)-1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Reduction of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid in methanol at 0° C. with sodium borohydride provided a mixture ofthe diastereomeric alcohols in ˜2:1 ratio. The residue was purified bysilica gel chromatography eluting with a gradient of isopropanol inhexanes. Fractions containing the major isomer were concentrated andthen lyophilized from acetonitrile/water to provide the title compoundas a fluffy white solid.

¹H NMR (500 MHz, Methanol-d4) δ ppm −0.29 (br s, 1 H), 0.20 (br s, 1 H),0.46 (br s, 1 H), 0.60 (br s, 1 H), 1.19 (br s, 3 H), 1.24-1.35 (m, 1H), 1.39 (s, 3 H), 2.10-2.29 (m, 2 H), 2.63 (d, J=13.69 Hz, 1 H), 2.82(br s, 1 H), 2.98 (d, J=13.94 Hz, 1 H), 3.40-3.50 (m, 1 H), 3.57 (br s,1 H), 4.82 (d, J=11.00 Hz, 1 H), 6.61-7.64 (m, 8 H). MS (ESI) m/z=490[M+H]⁺.

Example 2582-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-2-hydroxypropyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

L-Selectride (Aldrich, St. Louis, Mo.), (1M in THF, 5.0 ml, 5.00 mmol)was added dropwise over the course of 5 minutes to a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-oxopropyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

(Example 257, Step E, 1.035 g, 2.12 mmol) in THF (35 ml) at −78° C.After 90 min, the mixture was allowed to warm to 0° C. and was carefullyquenched by the addition of saturated ammonium chloride. The aqueousphase was extracted three times with ethyl acetate. The combined organiclayer was washed with 1 M HCl, water, sat. aq. NaCl solution and driedover sodium sulfate. After concentration in vacuo, the residue waspurified by silica chromatography eluting with a gradient of isopropanolin hexanes. Fractions containing the major isomer were concentrated andthen lyophilized from acetonitrile/water to provide the title compoundas a white powder. Stereochemistry assigned by analogy to Example 152.

¹H NMR (500 MHz, DMSO-d₆) δ −0.69 (br s, 1 H), −0.35 (br s, 1 H), 0.17(br s, 1 H), 0.36 (br s, 1 H), 1.07 (br s, 1 H), 1.27 (s, 4 H),1.98-2.23 (m, 2 H), 2.53-2.58 (m, 1 H), 2.93 (d, J=13.94 Hz, 1 H),3.36-3.49 (m, 1 H), 3.74-4.44 (m, 1 H), 4.46-5.11 (m, 2 H), 6.60-7.59(m, 8 H). MS (ESI) m/z=490 [M+H]⁺.

Example 2592-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(1-methylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)propane-2-sulfonamide

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 252, Step A, 59.3 mg, 0.129 mmol;) and isopropyl sulfonamide(48.7 mg, 0.395 mmol) were coupled by the procedure as described inExample 202, Step C to form the title compound isolated after silica gelchromatography as an off-white solid. MS (ESI) m/z=563 [M+H]⁺.

Step B:2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(1-methylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)propane-2-sulfonamide(Example 259, Step A) by a procedure similar to the one described inExample 71, Step F. The product was purified by reversed phase HPLC,eluting with 60 to 95% MeCN in water (0.1% TFA in both solvents). Highpurity fractions were combined, stripped of volatiles, and the resultingsolution was frozen and lyophilized to provide the title compound as anoff-white solid.

¹H NMR (500 MHz, CD₃OD) δ ppm −0.98-−0.71 (m, 1 H) −0.38-−0.16 (m, 1 H)0.12-0.29 (m, 1 H) 0.30-0.44 (m, 1 H) 1.31-1.39 (m, 6 H) 1.41 (s, 3 H)1.52-1.64 (m, 1 H) 2.08 (dd, J=13.69, 3.18 Hz, 1 H) 2.26 (br. s, 1 H)2.40 (t, J=13.69 Hz, 1 H) 2.70 (d, J=13.45 Hz, 1 H) 3.00 (d, J=13.20 Hz,1 H) 3.09 (dd, J=13.69, 3.42 Hz, 1 H) 3.25 (dt, J=13.51, 6.82 Hz, 1 H)3.33-3.34 (m, 1 H) 3.41 (ddd, J=13.75, 10.82, 3.06 Hz, 1 H) 3.96 (br s,1 H) 4.94 (d, J=11.00 Hz, 1 H) 6.98-7.18 (m, 5 H) 7.27 (br s, 3 H). MS(ESI) m/z=581 [M+H]⁺.

Example 2602-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclopropyl-2-(methylamino)ethyl)-3-methylpiperidin-2-one

(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylacetaldehyde(Example 252, Step B, 554 mg, 1.21 mmol) was taken up in 10 mL anhydroustoluene and stripped to dryness in vacuo twice to effect azeotropicremoval of trace moisture. After removal of residual solvents under highvacuum, the aldehyde was dissolved in dichloroethane (12 mL).Methylamine (2.0 M in THF, 6.1 mL, 12.20 mmol) and acetic acid (2 mL,35.0 mmol) were added to the solution which was stirred at ambienttemperature for about 30 minutes. Sodium triacetoxyborohydride (1.12 g,5.28 mmol) was added as a solid in a single portion and the mixture wasstirred at ambient temperature overnight. HPLC analysis showed thatepimerization had occurred to give both diastereomers. The reaction wasquenched with saturated sodium bicarbonate solution. The aminediastereomers were extracted into dichloromethane. The organic phase waswashed with water, and dried over sodium sulfate. After concentrationthe resulting residue gave a slightly turbid solution on redissolutionin ethyl acetate, and was consequently redried over magnesium sulfate.Concentration gave a mixture of diastereomers as a yellowish-white foam(577 mg). The two epimeric products were separated by SFC chromatography(250×30 mm Chiralpak® IC column (Chiral Technologies, Inc., WestChester, Pa., USA) with 42 g/min IPA and [20 mM NH₃] and 78 g/min CO₂.On concentration, the first eluting, epimer3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylamino)ethyl)-3-methylpiperidin-2-onewas obtained. Concentration of fractions containing the second elutingcomponent gave the title compound. MS (ESI) m/z=471 [M+H]⁺.

Step B:N—((R)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonamide

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclopropyl-2-(methylamino)ethyl)-3-methylpiperidin-2-one(Example 260, Step A, 168 mg, 0.356 mmol) was transferred as a solutionin 3 mL anhydrous toluene to an oven-dried 10 mL round bottom flask andthe solution was stripped to dryness on a rotary evaporator. This wasrepeated twice to effect azeotropic removal of trace moisture.Cyclopropanesulfonyl chloride and pyridine were added to the flask. Thereaction was monitored for completion by LC-MS. Ultimately 5×(0.15 mlsulfonyl chloride and 0.15 mL pyridine) were added over the course of 4days. Dichloromethane was added when solids began to appear. Thereaction mixture was diluted with ethyl acetate and citric acid solution(10%). The aqueous phase was washed twice with ethyl acetate. Thecombined organic layer was washed with sat. aq. NaCl solution and driedover sodium sulfate. After concentration in vacuo, the yellow residualoil was purified by chromatography on silica, eluting with a gradient ofethyl acetate in hexanes. Fractions containing the title compound werecombined and concentrated to give the title compound as a white foam. MS(ESI) m/z=575 [M+H]⁺

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((R)-1-cyclopropyl-2-(N-methylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained fromN—((R)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-methylcyclopropanesulfonamide(Example 260, Step B, 153 mg, 0.265 mmol) by a procedure similar to theone described in Example 71, Step F. The compound was purified byreverse phase HPLC on a Sunfire™ C18 column (Waters, Milford, Mass.),eluting with a gradient of 50 to 100% MeCN in water (0.1% TFA in bothsolvents), then further purified by SFC chromatography (250×30 mm Lux2®column (Phenomenex, Torrance, Calif. 90501, USA) with 32 g/min methanol[20 mM NH₃]+48 g/min CO₂ on Thar 80 SFC (Thar Technologies, Pittsburgh,Pa.). Outlet pressure=100 bar; Temp.=23 C; Wavelength=220 nm. Used 0.8mL injections of 95 mg/15 mL [6.3 mg/mL sample solution in methanol,i.e. 5.1 mg/injection]. Run time=6 min, Cycle time=3.5 min). Pooledfractions were concentrated to give the title compound as a white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ 0.14 (d, J=3.91 Hz, 2 H), 0.51 (t,J=5.26 Hz, 2 H), 0.93-1.11 (m, 2 H), 1.14-1.23 (m, 1 H), 1.25-1.28 (m, 1H), 1.46 (br s, 3 H), 1.52-1.76 (m, 2 H), 1.87-2.00 (m, 1 H), 2.20-2.39(m, 2 H), 2.72 (d, J=15.41 Hz, 4 H), 2.92-3.07 (m, 3 H), 3.13 (d,J=15.41 Hz, 1 H), 3.98 (dd, J=13.82, 11.13 Hz, 1 H), 4.93 (br s, 1 H),6.90 (d, J=5.87 Hz, 1 H), 7.00 (s, 1 H), 7.05-7.26 (m, 6 H). MS (ESI)m/z=593 [M+H]⁺.

Example 2612-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxy-4-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A: Methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate

Methyl methacrylate (82 mL, 773 mmol) was added to a solution of2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (195.2 g, 736 mmol;Example 1, Step A) in anhydrous THF (1.5 L) under an atmosphere ofnitrogen. A suspension of potassium t-butoxide (8.26 g, 73.6 mmol) inanhydrous THF (340 mL) (sonicated to break up the solids) was thenprepared and cannulated into the solution containing the2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone. The solution was cooledto ˜16° C. and the orange colored solution was left to stir at ambienttemperature for 2.5 d. (After 2 d TLC shows the absence of the startingmaterial). The mixture was concentrated under vacuum. The residualreddish brown oil was diluted with ethyl acetate (900 mL) and washedwith water (4×190 mL) and then sat. aq. NaCl solution. The organic layerwas dried over magnesium sulfate and concentrated under reduced pressureto provide the title compound as a racemic mixture of diastereomers.

¹H-NMR (500 MHz, CDCl₃) δ 7.88 (m, 4H), 7.39 (m, 2H), 7.27-7.12 (seriesof m, 4H), 4.62 (dd, J=9.0, 5.6 Hz, 0.5H), 4.59 (dd, J=9.3, 5.4 Hz,0.5H), 3.69 (s, 1.5H), 3.60 (s, 1.5H), 2.46 (m, 1H), 2.33 (m, 1H), 2.08(ddd, J=13.9, 9.3, 5.4 Hz, 0.5 H), 1.97 (ddd, J=13.7, 9.0, 4.4 Hz,0.5H), 1.23 (d, J=6.9 Hz, 1.5 H), 1.16 (d, J=7.1 Hz, 1.5H) ppm.

Step B: Racemic mixture of (4R,5R)-methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate(4S,5S)-methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate

Anhydrous methanol (600 mL) was placed in a 3 L three-neckedround-bottomed flask equipped with a stir bar and temperature probeunder an atmosphere of N₂ and cooled to about −20° C. Sodium borohydride(26.2 g, 693 mmol) was added in 5 g portions. Via an addition funnel, asolution of methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (253 g,693 mmol; Example 261, Step A) in methanol (600 mL) was added dropwiseto the reaction, maintaining a temperature between −27° C. to −30° C.The reddish solution was stirred at −30° C. for 30 minutes and thenallowed to warm to −15° C. The reaction was monitored for completion byTLC. The reaction was quenched by slowly adding water (68.6 mL, 3.8 mol)through the addition funnel. The mixture was allowed to warm to ambienttemperature. Solvents were removed under vacuum. The residual yellowishoil was diluted in ethyl acetate (1.2 L) and washed with water (400 mL).The organic layer was washed with sat. aq. NaCl solution (2×300 mL),forming an emulsion. After waiting for the most of the emulsion toseparate, the organic layer was dried over magnesium sulfate. Thesolution was filtered through filter paper and concentrated under vacuumto provide a racemic mixture of diastereomers.

¹H-NMR (500 MHz, DMSO-d6) δ 7.33 (m, 2H), 7.27-7.17 (series of m, 5H),7.04 (m, 1H), 5.43 (d, J=4.4 Hz, 0.5H), 5.37 (d, J=4.6 Hz, 0.5H), 4.77(t, J=5.4 Hz, 0.5H), 4.71 (dd, J=6.6, 4.9 Hz, 0.5H), 5.33 (s, 1.5H),3.46 (s, 1.5H), 2.87 (dt, J=10.2, 4.7 Hz, 0.5H), 2.75 (ddd, J=11.2, 6.6,4.9 Hz, 0.5H), 2.04 (m, 1.5H), 1.71 (m, 1H), 1.46 (m, 0.5H), 0.97 (d,J=6.6 Hz, 1.5H), 0.94 (d, J=7.1 Hz, 1.5H) ppm. TLC (20% EtOAc/Hexane)R_(f)=0.34.

Step C.(4R,5R)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoicacid and(4S,5S)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoicacid

A solution of the racemic mixture of (4R,5R)-methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate and(4S,5S)-methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoate(245.7 g, 669 mmol; Example 261, Step B) in THF (1.17 L) was prepared bywarming to 40° C. The flask was cooled to ˜14° C., internal temperature.A solution of lithium hydroxide hydrate (42.1 g, 1.0 mol) in water (585mL) was cautiously added to the THF solution. The mixture was left tostir at ambient temperature and monitord by LC/MS for the absence ofstarting material (˜2.5 h). Upon completion, the solution was againcooled to a temperature of ˜14° C. 2N HCl (526 mL) was added slowly. Thelayers were partitioned and the aqueous layer (pH ˜2) was washed withethyl acetate (1×500 mL then 1×250 mL). The combined organic layers weredried over magnesium sulfate and concentrated to afford 264 g of aracemic mixture of(4R,5R)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoicacid and(4S,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoicacid was obtained. The crude material containing some residual solventwas used as-is in the subsequent transformation. The product (estimatedafter solvent correction 227 g) is a roughly 1:1 mixture ofdiastereomers at the 2-position.

¹H-NMR (500 MHz, CDCl₃) δ 7.31 (m, 2H), 7.25 (m, 3H), 7.17 (m, 2H), 7.05(m, 1H) 4.74 (m, 1H), 2.99 (ddd, J=11.2, 1.7, 3.7 Hz, 0.5H), 2.90 (ddd,J=11.5, 7.3, 4.6 Hz, 1H), 2.15 (m, 1.5H), 1.85 (m, 0.5 H), 1.67 (ddd,J=14.3, 11.5, 3.4 Hz, 0.5H), 1.52 (m, 0.5 H), 1.08 (d, J=7.1 Hz, 1.5 H),1.05 (d, J=6.9 Hz, 1.5H) ppm.

Alternatively,(4R,5R)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoicacid, as a mixture of methyl diastereomers, can be prepared from racemicmethyl 4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate.

In a three-neck flask, a solution of racemic methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (500 g,1.37 mol, 1 eq) in anhydrous 2-propanol (2.5 L) was charged withKO^(t)Bu (46.1 g, 0.41 mol, 0.3 eq) and stirred for 30 min until a clearyellow solution was formed. The solution was then treated with asolution of dichloro{(S)-(−)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II)(5 g, 4.1 mmol, 0.003 eq, Strem Chemicals inc., Newburyport, Mass.) inanhydrous toluene (250 mL) and stirred at RT for 2 hours (Note: Most ofmethyl ester was converted to isopropyl). The solution was transferredto two Parr shakers, sealed and purged with hydrogen 3 times. Thereaction was shaken at RT under 414 kilopascals hydrogen pressure. After18 hrs, the reaction was quenched with sat. NH₄Cl, concentrated andextracted with EtOAc (2 L×2). The combined organics was washed withbrine and concentrated as a brown oil and used as such in the next step.

The crude intermediate (542 g, 1.37 mol) was dissolved in THF (3 L) andMeOH (1 L) and charged with 2 M LiOH (1 L). The solution was rotated atRT overnight, concentrated to remove most of THF and MeOH, and quenchedwith 1 L of 2 M HCl. After phase separation, the aqueous layer wasextracted with EtOAc (1 L×2). The combined organics were washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.This product,(4R,5R)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-hydroxy-2-methylpentanoicacid, as a mixture of methyl diastereomers, was taken crude to the nextstep.

Step D.(5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-oneand(5S,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one

The mixture of hydroxy acid diastereomers (227 g, 643 mmol; Example 261,Step C) was lactonized under Dean-Stark conditions in toluene (1.07 L)with pyridine 4-methylbenzenesulfonate (PPTS, 4.84 g, 19.28 mmol) underan atmosphere of nitrogen. After 2 h of vigorous reflux the solution wascooled to ambient temperature and transferred to a separatory funnel.The flask residue was rinsed in with ethyl acetate. The combined organicphase was washed in succession with water (1×250 mL), sat. sodiumbicarbonate solution (1×250 mL), and sat. aq. NaCl solution (1×250 mL).After drying with magnesium sulfate, concentration under reducedpressure provides a mixture of diastereomeric lactones as a light brownsolid.

¹H-NMR (500 MHz, CDCl₃) δ 7.24-6.95 (series of m, 6H), 6.91 (d, J=7.6Hz, 0.5H), 6.82 (m, 1.5H), 6.73 (d, J=7.6 Hz, 0.5H), 5.77 (d, J=3.9 Hz,0.5H), 5.69 (d, J=4.6 Hz, 0.5H), 3.67 (dt, J=7.6, 4.2 Hz, 0.5H), 3.55(td, J=7.8, 4.6 Hz, 0.5H), 2.97 (m, 0.5 H), 2.81 (doublet of quintets,J=14.4, 7.1 Hz, 0.5 H), 2.56 (dt, 16.1, 8.0 Hz, 0.5H), 2.32 (dt, J=13.7,6.9 Hz, 0.5H), 2.07 (ddd, J=13.2, 8.6, 4.4 Hz, 0.5H), 1.85 (ddd, J=14.2,12.7, 7.6 hz, 0.5H), 1.41 (d, J=7.1 Hz, 1.5H), 1.39 (d, J=6.9 Hz, 1.5H)ppm.

Step E:(3S,5R,6R)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-oneand(3R,5S,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one

A solution of racemic lactone from the previous step (Example 261, StepD, 190.28 g, 568 mmol) in THF (946 mL) was prepared in a 1 neck roundbottomed flask equipped with a Claisen adapter, 500 mL dropping funnel,and internal temperature probe under an atmosphere of nitrogen. Thesolution was cooled to a temperature of −35° C. Allyl bromide (120 mL,1.42 mol) was added via the addition funnel, maintaining the temperaturebelow −30° C. during addition. A solution of LHMDS (1M in THF, 738 mL,738 mmol) was added dropwise to the reaction, maintaining thetemperature below −30° C. The reaction was allowed to slowly warm to −5°C. over a period of 1 h. The solution was recooled to about −20° C. andadded via cannula into a solution of ammonium chloride in water at about5 C. After separation of the layers, the aqueous layers were extractedtwice with ethyl acetate. The combined organic layers were washed withsat. aq. NaCl solution and dried over sodium sulfate. Concentrationunder vacuum provided 219 g of a light yellow solid. The solids wereslurried at ambient temperature for 2 h with hexane (2 L). The solidswere then collected by filtration, rinsed with hexane (2×100 mL) anddried to provide the title compounds as a racemic mixture.

¹H-NMR (500 MHz, CDCl₃) δ 7.24 (m, 1H), 7.20-7.15 (m, 3H), 6.91 (t,J=1.7 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H), 6.59 (m, 2H), 5.84 (ddt, J=17.6,10.3, 7.6 Hz, 1H), 5.71 (d, J=5.4 Hz, 1H), 5.21-5.13 (m, 2H), 3.81 (dt,J=12.0, 4.2 Hz, 1H), 2.62 (ABX J_(AB)=14.0, J_(AX)=7.8 Hz, 1H), 2.52(ABX, J_(AB)=13.9, J_(AX)=7.3 Hz, 1H), 1.98 (dd, J=14.0, 12.0 Hz, 1H),1.91 (ddd, J=14.0, 3.7, 1.2 Hz, 1H), 1.42 (s, 3H) ppm.

Step F: Separation of(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-oneand(3R,5S,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one

A racemic mixture of(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-oneand(3R,5S,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-onecan be separated using chiral Supercritical

Fluid Chromatography (SFC) as follows: Using a 250×30 mm Lux2® column(Phenomenex, Torrance, Calif. 90501, USA) with 20 g/min methanol (20 mMNH3)+60 g/min CO₂ on a Thar 80 SFC. Outlet pressure=100 bar; Temp.=23 C;Wavelength=220 nm. Used 0.3 mL injections of 5.0 g/80 mL (62.5 mg/mLsample solution in methanol/dichloromethane (75:5), i.e. 18.75mg/injection. Run time=8 min, Cycle time=3 min.

The first peak collected was assigned as(3R,5S,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one.The second peak collected was determined to be(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-oneby subsequent chemical derivatization with (S)-2-amino-1-butanol andconversion to the same compound as prepared in Example 91, Step B, bythe procedures described for Example 261, Steps G and H. The NMR of theseparated enantiomers was consistent with the spectrum of the racematedescribed above.

Alternatively,(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-onecan be prepared from racemic methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate.

In a three-neck flask, a solution of racemic methyl4-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-5-oxopentanoate (500 g,1.37 mol, 1 eq) in anhydrous 2-propanol (2.5 L) was charged withKO^(t)Bu (46.1 g, 0.41 mol, 0.3 eq) and stirred for 30 mins until aclear yellow solution was formed. The solution was then treated with asolution of Dichloro{(S)-(−)-2,2′-bis[di(3,5-xylyl)phosphino]-1,1′-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]ruthenium(II)(5 g, 4.1 mmol, 0.003 eq,/Strem Chemicals Inc., Newburyport, Mass.) inanhydrous toluene (250 mL) and stirred at RT for 2 hours (Note: Most ofmethyl ester was converted to isopropyl). The solution was transferredto two Parr shakers, sealed and purged with hydrogen 3 times. Thereaction was shaken at RT under 414 kilopascals hydrogen pressure. After18 hrs, the reaction was quenched with sat. NH₄Cl, concentrated andextracted with EtOAc (2 L×2). The combined organics was washed withbrine and concentrated as a brown oil and used as such in the next step.

The crude intermediate (542 g, 1.37 mol) was dissolved in THF (3 L) andMeOH (1 L) and charged with 2 M LiOH (1 L). The solution was rotated atRT overnight, concentrated to remove most of THF and MeOH, and quenchedwith 1 L of 2 M HCl. After phase separation, the aqueous layer wasextracted with EtOAc (1 L×2). The combined organics was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.

Step G:(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N—((S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide

A mixture of (S)-2-amino-3-methylbutan-1-ol (550 mg, 5.33 mmol) and(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one(Example 261, Step H, 2^(nd) compound, 500 mg, 1.332 mmol) was heated to100° C. for 24 h. After cooling to room temperature, the residue wasdissolved in ethyl acetate and washed 3× with 1N HCl (5 mL) followed bysat. aq. NaCl solution (5 mL). The organic phase was dried over MgSO₄,filtered, and the filtrate was concentrated to afford the titlecompound.

¹H-NMR (500 MHz, DMSO-d₆) δ 7.21 (m, 2H), 7.10 (m, 2H), 7.06 (br s, 1H),6.99 (m, 2H), 6.86 (br d, J=8.8 Hz, 1H), 6.84 (br d, J=7.1 Hz, 1H), 5.53(dddd, J=16.9, 10.3, 8.1, 6.6 Hz, 1H), 5.46 (d, J=4.4 Hz, 1H), 4.90 (m,2H), 4.78 (t, J=4.2 Hz, 1H), 4.56 (t, J=5.1 Hz, 1H), 3.56 (m, 1H), 3.37(m, 2H), 2.87 (dt, J=7.8, 4.2 Hz, 1H), 2.29 (dd, J=13.7, 6.4 Hz, 1H),2.14 (dd, J=14.4, 7.8 Hz, 1H), 1.97 (dd, J=14.4, 3.9 Hz, 1H), 1.88 (dd,J=13.9, 8.1 Hz, 1H), 1.76 (octet, J=6.4 Hz, 1H), 0.97 (s, 3H), 0.81 (d,J=6.8 Hz, 3H), 0.75 (d, J=6.6 Hz, 3H) ppm.

Step H.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one

(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N—((S)-1-hydroxy-3-methylbutan-2-yl)-2-methylpent-4-enamide(example 261, step G) was transferred as a solution in anhydrous benzeneto a pre-weighed, oven-dried 50 mL round bottom flask and stripped todryness. Azeotropic distillation of benzene/water was performed twicemore, and the residue was dried under high vacuum for 2 h, after whichit weighed 550 mg. An oven-dried stir bar was added to the flask. Thevessel was sealed and purged with nitrogen and then anhydrousdichloromethane (23 mL) was added, followed by triethylamine (1.3 mL,9.33 mmol). The resulting stirred solution was cooled to 0° C.Methanesulfonyl chloride (0.270 mL, 3.49 mmol) was added dropwise bymicrosyringe. After 1 h, the reaction was quenched by addition of HCl(1.2M, 12 mL) and diluted in ethyl acetate. The organic layer was washedwith 1.2 M HCl (30 mL), saturated sodium bicarbonate (2×25 mL), and sat.aq. NaCl solution. After drying over magnesium sulfate and concentrationin vacuo an intermediate was obtained as an off-white foam (0.64 g,).1,8-Bis(dimethylamino)naphthalene, 314 mg, 1.465 mmol) and water (0.104mL, 5.75 mmol) were added to the intermediate, followed by dioxane (23mL). The mixture was heated under nitrogen at 110° C. overnight. Aftercooling, the mixture was dissolved in ethyl acetate and washed withsaturated ammonium chloride solution.

The aqueous phase was back-extracted with ethyl acetate. The combinedorganic layers were washed with sat. aq. NaCl solution, dried oversodium sulfate, filtered, and concentrated in vacuo. The residue waspurified by chromatography on silica, eluting with ethyl acetate inhexanes. Chromatography fractions containing predominantly the desiredproduct were combined. The product was re-purified by chromatography ona 40 g silica column, eluting with a gradient of 0 to 50% ethyl acetatein hexanes to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ 0.73 (d, J=6.46 Hz, 3 H), 0.83 (d,J=6.65 Hz, 3 H), 1.28 (s, 3 H), 1.91-2.00 (m, 1 H), 2.00-2.10 (m, 1 H),2.26-2.45 (m, 1 H), 2.56-2.74 (m, 2 H), 3.16 (br. s., 1 H), 3.26 (ddd,J=13.50, 10.47, 3.42 Hz, 1 H), 3.43 (br. s., 1 H), 3.76 (dd, J=11.25,3.42 Hz, 1 H), 4.49 (d, J=10.56 Hz, 1 H), 5.18 (s, 1 H), 5.21 (d, J=6.46Hz, 1 H), 5.87 (ddt, J=16.95, 9.85, 7.53 Hz, 1 H), 6.72 (apparent d,J=7.63 Hz, 1 H), 6.95 (t, J=1.66 Hz, 1 H), 6.97-7.17 (m, 4 H), 7.23 (d,J=8.41 Hz, 2 H). MS (ESI) m/z=460 [M+H]⁺.

Step I.(S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutanal

Dess-Martin periodinane (938 mg, 2.212 mmol) was added as a solid to asolution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one(Example 261, Step H, 365.4 mg, 0.794 mmol) in dichloromethane (8 mL)and water (0.04 mL, 2.220 mmol). The resulting suspension was vigorouslystirred at ambient temperature for 1.5 h. The reaction was quenched withsodium thiosulfate solution (1M aq, 6 mL). Additional sodium thiosulfatesolution (1M aq, 6 mL) was added and stirred until the chalky suspensionbecame a slightly cloudy biphasic mixture. The aqueous phase wasseparated and back extracted with dichloromethane. The organic layer waswashed with sodium thiosulfate solution, saturated aqueous sodiumbicarbonate and sat. aq. NaCl solution. After drying over sodium sulfateand concentration, the residue was purified on silica gel, eluting witha gradient of 0 to 30% ethyl acetate in hexanes. Fractions containingthe desired product were pooled to give the title compound as a whitefoam. MS (ESI) m/z=458 [M+H]⁺.

Step J.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-4-methylpentan-3-yl)-3-methylpiperidin-2-one

Methylmagnesium bromide (1.4 mL, 1.960 mmol, 1.4 M in 1:3 THF:toluene)was added by syringe to a solution under nitrogen of pre-dried(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutanal(Example 261, Step 1,286 mg, 0.624 mmol) in THF (6.5 mL) at 0° C. Theice bath was removed. After 2 h, the solution was recooled to 0° C. andquenched by careful addition of saturated ammonium chloride solution.The resulting mixture was extracted with ethyl acetate. The organiclayer was washed with sat. aq. NaCl solution, dried over sodium sulfate,filtered, and concentrated. The residue was purified by chromatographyon silica, eluting with a gradient of 0 to 40% ethyl acetate in hexanes.Fractions containing the desired product were combined and re-purifiedto give the title compound as a mixture of diastereomeric alcohols) as awhite foam. MS (ESI) m/z=474 [M+H]⁺.

Step K.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-methyl-4-oxopentan-3-yl)-2-oxopiperidin-3-yl)aceticacid

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-hydroxy-4-methylpentan-3-yl)-3-methylpiperidin-2-one(Example 261, Step J, 244 mg, 0.51 mmol) was converted by a proceduresimilar to the one described in Example 257, Step E to the titlecompound obtained after silica gel chromatography eluting with ethylacetate in hexanes as a white solid. MS (ESI) 490 [M+H]⁺.

Step L.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxy-4-methylpentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained from2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-((S)-2-methyl-4-oxopentan-3-yl)-2-oxopiperidin-3-yl)aceticacid (Example 261, Step K, 79.9 mg, 0.16 mmol) by a procedure similar tothe one described in Example 258. After workup, the material waspurified by chromatography on a 24 g silica column, eluting with agradient of 10 to 20% isopropanol in hexanes. The purest fractions werecombined, concentrated, re-dissolved in 1:1 MeCN/water, passed through apall microfilter, frozen, and lyophilized to give the title compound asa white solid. Stereochemistry assigned by analogy to example 152.

¹H NMR (400 MHz, Methanol-d4) δ 0.62 (d, J=7.04 Hz, 3 H), 0.67 (d,J=6.65 Hz, 3 H), 1.26 (d, J=6.46 Hz, 3 H), 1.42 (s, 3 H), 2.13-2.29 (m,3 H), 2.49 (t, J=7.14 Hz, 1 H), 2.62 (d, J=13.69 Hz, 1 H), 3.01 (d,J=13.69 Hz, 1 H), 3.57 (td, J=10.81, 6.16 Hz, 1 H), 4.23 (t, J=6.65 Hz,1 H), 4.70 (d, J=10.95 Hz, 1 H), 6.65-7.51 (m, 8 H). MS (ESI) m/z=492[M+H]⁺.

Example 2622-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(pyridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(pyridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(1S,2R)-4-Carboxy-2-(3-chlorophenyl)-1-(4-chlorophenyl)butan-1-aminiumchloride

A suspension of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (Example 1,Step E, 29 g, 91 mmol) in 5 M hydrochloric acid (91 mL, 453 mmol) wasbrought to reflux. After 2 h, TLC indicated complete consumption ofstarting material to the ring opened product (elution with 75% ethylacetate in hexanes; R_(f) starting material=0.5, R_(f) product=0.0). Thereaction contents were co-distilled with toluene (4×100 mL) then broughtto dryness. Solids were suspended in diethyl ether (100 mL), filtered,and washed with ether (100 mL). The white crystalline solid was broughtto dryness under high vacuum to provide the title compound.

¹H NMR (500 MHz, DMSO-d₆) δ 7.31-7.39 (m, 2H), 7.24-7.30 (m, 2H),7.10-7.23 (m, 3H), 6.90-7.01 (m, 1H), 4.65 (d, J=10.03 Hz, 1H), 3.27(dt, J=3.67, 10.51 Hz, 1H), 2.25-2.36 (m, 1H), 1.95-2.10 (m, 1H),1.77-1.94 (m, 2H).

Step B.(4R,5S)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-(cyclopropyl(pyridin-2-yl)methylamino)pentanoicacid

Cyclopropyl(pyridin-2-yl)methanone (0.393 g, 2.67 mmol) [Meijer, LouisH. P. et al., Tetrahedron, 40, 5185 (1984)] was mixed with neattetra-isopropoxy-titanium (0.782 mL, 2.67 mmol) and stirred at roomtemperature for 20 min.(1S,2R)-4-carboxy-2-(3-chlorophenyl)-1-(4-chlorophenyl)butan-1-aminiumchloride (0.500 g, 1.334 mmol; Example 262, Step A) was added as a solidand stirred overnight. Methanol (13 mL) was added followed by carefuladdition of sodium borohydride (0.151 g, 4.00 mmol). The resultingsolution was stirred at room temperature for 10 min. The reaction wasquenched with HCl (1 N aq.), extracted with dichloromethane and washedwith sat. aq. NaCl solution. The combined organic layer was dried oversodium sulfate and concentrated to provide a crude product used in thenext step without further purification.

Step C.(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(pyridin-2-yl)methyl)piperidin-2-oneor(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(pyridin-2-yl)methyl)piperidin-2-one

The crude product from Example 162, Step B was dissolved indichloroethane (13 mL) in the presence of 4 Å molecular sieves (15pieces) and heated at reflux overnight. The reaction was filteredthrough Celite® (J.T. Baker, Phillipsberg, N.J., diatomaceous earth),rinsed with dichloromethane and concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC (eluent: 10 to 90%acetonitrile, water, 0.1% TFA, gradient elution) to give the titlecompound as the first eluting diastereomer.

Step D.(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(pyridin-2-yl)methyl)-3-methylpiperidin-2-oneor(5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(pyridin-2-yl)methyl)-3-methylpiperidin-2-one

A solution of LHMDS (1M in THF, 0.585 mL, 0.585 mmol) was added to asolution of the compound from Example 262, Step C (0.220 g, 0.487 mmol)and iodomethane (0.040 mL, 0.634 mmol) in THF (5.0 mL) at −78° C. Thereaction was allowed to warm to ambient temperature, then was quenched(sat. aqueous NH₄Cl solution), extracted (2×EtOAc), and washed (sat. aq.NaCl solution). The combined organic layers were dried over sodiumsulfate and concentrated under reduced pressure. The crude material wasabsorbed onto a plug of silica gel and purified by chromatography (SiO₂,40 g, eluting with 20% to 60% ethyl acetate in hexane) to provide thetitle compound as a mixture of diastereomers.

Step E.(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(pyridin-2-yl)methyl)-3-methylpiperidin-2-oneor(5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4R)-cyclopropyl(pyridin-2-yl)methyl)-3-methylpiperidin-2-one

A solution of LHMDS (1.0M in THF, 0.838 mL, 0.838 mmol) was added to asolution of the diastereomeric mixture from Example 262, Step D (0.130g, 0.279 mmol) and allyl bromide (0.095 mL, 1.117 mmol) in THF (2.80mL). The reaction mixture was stirred at room temperature for 5 min,then heated to 50° C. for 3 h. The solution was diluted with sat. NH₄Clsolution, extracted (2×ethyl acetate), and washed (sat. aq. NaClsolution). The combined organic layers were dried over sodium sulfateand concentrated under reduced pressure. The crude material was absorbedonto a plug of silica gel and purified by chromatography (SiO₂, 40 g,eluted with a gradient of 0 to 35% EtOAc in hexane) to provide the titlecompound as a mixture of diastereomers as a white foam.

Step F.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-cyclopropyl(pyridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((R)-cyclopropyl(pyridin-2-yl)methyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The compound of Example 262, Step E (90 mg, 0.178 mmol) was treated by aprocedure similar to the one described in Example 71, Step F. Separationof the diastereomers by reverse phase preparatory HPLC (eluent: 10 to90% acetonitrile, water, 0.1% TFA, gradient elution) gave the titlecompound as the first eluting diastereomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.09 (br s, 1H) 0.28-0.34 (m, 1 H)0.77-0.95 (m, 2 H) 1.37 (s, 3 H) 1.51-1.66 (m, 1 H) 2.13 (dd, J=14.09,3.13 Hz, 1 H) 2.28 (t, J=13.69 Hz, 1 H) 2.79 (d, J=15.06 Hz, 1 H) 2.98(d, J=15.06 Hz, 1 H) 3.29-3.41 (m, 1 H) 4.83 (d, J=9.98 Hz, 1 H) 5.08(d, J=10.37 Hz, 1 H) 6.80 (d, J=7.63 Hz, 1 H) 6.96 (m, 5 H) 7.04-7.17(m, 2 H) 7.63 (d, J=8.22 Hz, 1 H) 7.72 (t, J=6.65 Hz, 1 H) 8.07 (t,J=7.24 Hz, 1 H) 9.06 (d, J=4.89 Hz, 1 H). MS (ESI) m/z=523.2 (M+1).

Example 2632-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.2-((3R,5R,6S)-1-((S)-2-((tert-Butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a rapidly stirring solution of(3S,5R,6S)-3-allyl-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(1450 mg, 2.08 mmol; Example 251, Step D) in a mixture of water (11 mL),acetonitrile (7.2 mL), and CCl₄ (7.2 mL) was added sodium periodate(1780 mg, 8.32 mmol), followed by ruthenium (III) chloride hydrate (47mg, 0.21 mmol). After being stirred vigorously for 16 h, additionalwater (5.4 mL), acetonitrile (3.6 mL), and CCl₄ (3.6 mL) were added andto the resulting clear dark solution as was added additional sodiumperiodate (890 mg, 4.16 mmol) and ruthenium (III) chloride hydrate (24mg, 0.10 mmol). After being stirred vigorously for additional 4 h, thereaction was acidified (10% citric acid) and diluted (EtOAc). Thereaction mixture was filtered through pad of Celite® (J.T. Baker,Phillipsberg, N.J., diatomaceous earth) and the filtrate was extracted(2×EtOAc). The combined organic layers were washed (brine), dried(Na₂SO₄), and concentrated under the reduced pressure. Purification ofthe residue by chromatography on silica gel (80 g SiO₂, 30%, 40%, and50% EtOAc/Hex) provided the title compound as a pale yellow foam.

Step B. Methyl2-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate

To a solution of2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (1400 mg, 1.96 mmol; Example 263, Step A) in a mixture of MeOH (3.1mL) and benzene (12.5 mL) was added 2.0 M (trimethylsilyl)diazomethanein hexanes (1.96 mL, 3.92 mmol) at 0° C. dropwise. After being stirredat 0° C. for 1 h, the reaction was concentrated under reduced pressure.Purification of the residue by chromatography on silica gel (40 g SiO₂,10%, and 20% EtOAc/Hex) provided the title compound as a pale yellowfoam.

Step C. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate

To a solution of methyl2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(578 mg, 0.793 mmol; Example 263, Step B) in THF (3.2 mL) was added 1 MTBAF in THF (2.38 mL, 2.38 mmol) at 0° C. and the reaction mixture wasallowed to warm to rt. After being stirred at rt for 6 h, the reactionwas quenched (sat. NH₄Cl), extracted (2×EtOAc) and washed (brine). Thecombined organic layers were dried (Na₂SO₄) and concentrated under thereduced pressure. Purification of the residue by chromatography onsilica gel (40 g SiO₂, 10% and 50% EtOAc/Hex) provided the titlecompound as a colorless foam.

Step D. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetate

To a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate(100 mg, 0.184 mmol; Example 263, Step C) andcyanomethylenetributylphosphorane (177 μL, 0.734 mmol) in toluene (0.92mL) was added thiophene-2-sulfonamide (90 mg, 0.55 mmol) and theresulting solution was stirred at 35° C. overnight. The reaction wasquenched (sat. NH₄Cl), extracted (2×EtOAc), and washed (brine). Thecombined organic layers were dried (Na₂SO₄) and concentrated under thereduced pressure. Purification of the residue by chromatography onsilica gel (24 g SiO₂, 35% EtOAc/Hex) provided the title compound as apale yellow foam.

Step E.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetate(30 mg, 0.048 mmol; Example 263, Step D) in a mixture of water (0.16mL), MeOH (0.16 mL), and THF (0.16 mL) was added 2 M aq. LiOH (48 μL,0.095 mmol) at rt and the resulting solution was stirred at rt for 5 h.The reaction was quenched (sat. NH₄Cl), extracted (2×EtOAc), and washed(brine). The combined organic layers were dried (Na₂SO₄) andconcentrated under the reduced pressure. Purification of the residue bychromatography on silica gel (12 g SiO₂, gradient elution of 50% to 100%EtOAc in Hex and 30% iPrOH/DCM) provided the title compound as a whitepowder.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.50-7.66 (2 H, m), 6.95-7.25 (8 H,m), 6.81 (1 H, d, J=7.4 Hz), 5.66 (1H, br, s), 4.87 (1 H, d, J=10.0 Hz),3.05-3.26 (3 H, m), 2.87-3.02 (2 H, m), 2.78-2.84 (1 H, m), 2.18-2.32 (1H, m), 2.04-2.15 (1 H, m), 1.47 (3 H, s), 1.06-1.18 (1 H, m), 0.41-0.57(2 H, m), −0.02-0.10 (1 H, m), −0.35-−0.20 (1 H, m); MS (ESI) 621.0[M+H]⁺.

Example 2642-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylthiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(thiophene-2-sulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)acetate(31 mg, 0.049 mmol; Example 263) in DMF (0.25 mL) was added sodiumhydride (60% dispersion in mineral oil; 6 mg, 0.15 mmol) at rt, and thesolution was stirred for 10 min. Then iodomethane (28 mg, 0.20 mmol) wasadded and the resulting solution was stirred at rt for 5 h. The reactionwas quenched (sat. NH₄Cl), extracted (2×EtOAc), and washed (brine). Thecombined organic layers were dried (Na₂SO₄) and concentrated under thereduced pressure provided a mixture of the title compound and methylester.

To a solution of this crude mixture in water (0.16 mL), MeOH (0.16 mL),and THF (0.16 mL) was added lithium hydroxide (2.4 mg, 0.098 mmol) at rtand the resulting solution was stirred at RT overnight. The reaction wasquenched (sat. NH₄Cl), extracted (2×EtOAc) and washed (brine). Thecombined organic layers were dried (Na₂SO₄) and concentrated underreduced pressure. Purification of the residue by chromatography onsilica gel (4 g SiO₂, 50% and 90% EtOAc/Hex) provided the title compoundas a white powder.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.50-7.68 (2 H, m), 7.23-7.27 (2 H, m),7.12-7.22 (4 H, m), 6.88-7.02 (3 H, m), 4.86 (1 H, d, J=10.0 Hz),2.98-3.24 (2 H, m), 2.70-2.96 (3 H, m), 2.80 (3 H, s), 2.35-2.50 (2 H,m), 1.96-2.04 (1 H, m), 1.54 (3 H, br, s), 1.29-1.39 (1 H, m), 0.15-0.50(2 H, m), −0.41-−0.15 (1 H, m), −0.95-−0.65 (1 H, m); MS (ESI) 635.0[M+H]⁺.

Example 2652-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(5-chlorothiophene-2-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 263, Step C) by procedures similar to those described inExample 263, Step D and E, substituting thiophene-2-sulfonamide in StepD with the appropriate amount of 5-chlorothiophene-2-sulfonamide.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.35 (1 H, d, J=4.1 Hz), 6.97-7.25 (7 H,m), 6.94 (1 H, d, J=4.1 Hz), 6.78 (1 H, d, J=7.4 Hz), 5.82 (1 H, br, s),4.86 (1 H, d, J=10.0 Hz), 2.87-3.20 (5 H, m), 2.78-2.85 (1 H, m),2.19-2.27 (1 H, m), 2.07-2.16 (1 H, m), 1.46 (3 H, s), 1.01-1.13 (1 H,m), 0.50-0.60 (2 H, m), 0.06-0.17 (1 H, m), −0.25-−0.10 (1 H, m); MS(ESI) 655.0 [M+H]⁺, 652.9 [M−H]⁻.

Example 2662-((3R,5R,6S)-1-((S)-2-(5-Chloro-N-methylthiophene-2-sulfonamido)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from the methyl ester precursor of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(5-chlorothiophene-2-sulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 265) by a procedure similar to the one described inExample 264.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.28-7.40 (2 H, m), 6.83-7.18 (8 H, m),4.75-4.88 (1 H, m), 3.00-3.21 (2 H, m), 2.74-2.86 (2 H, m), 2.81 (3H,s), 2.25-2.54 (2 H, m), 1.95-2.05 (1 H, m), 1.57-1.84 (2 H, m), 1.53 (3H, br, s), 0.18-0.55 (2 H, m), −0.46-−0.15 (1 H, m), −0.95-−0.65 (1 H,m); MS (ESI) m/z=669.0 [M+H]⁺, 667.0 [M−H]⁻.

Example 2672-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(difluoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-2-methylpropane-2-sulfonamide

The title compound was obtained from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(300 mg, 0.654 mmol; Example 252, Step A) and2-methylpropane-2-sulfonamide (189 mg, 1.37 mmol) by a procedure similarto the one described in Example 127, Step F reacting for a total of 21h. Purification of the residue by chromatography on silica gel (40 gSiO₂, 30% and 50% EtOAc/Hex) provided the title compound as a paleyellow foam.

Step B.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(difluoromethyl)-2-methylpropane-2-sulfonamide

To a solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-2-methylpropane-2-sulfonamide(88 mg, 0.152 mmol; Example 267, Step A) in DMF (1.0 mL) was added 60%sodium hydride in mineral oil (24 mg, 0.61 mmol) and the resultingsolution was stirred at rt for 10 min. Then chlorodifluoromethane wasbubbled into the reaction for 10 min while the reaction was vigorouslystirred and the resulting reaction was stirred for 2 h. The reaction wasquenched (sat. NH₄Cl), extracted (2×EtOAc) and washed (brine). Thecombined organic layers were dried (Na₂SO₄) and concentrated under thereduced pressure. Purification of the residue by chromatography onsilica gel (12 g SiO₂, 20% and 30% EtOAc/Hex) provided the titlecompound as a colorless film.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(difluoromethyl)-2-methylpropan-2-ylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(difluoromethyl)-2-methylpropane-2-sulfonamide(57 mg, 0.091 mmol; Example 267, Step B) by a procedure similar to theone described in Example 71, Step F. Purification of the residue byreverse phase preparatory HPLC (Gemini™ Prep C₁₈ 5 um column,Phenomenex, Torrance, Calif.; gradient elution of 50% to 75% MeCN inwater, where both solvents contain 0.1% TFA) provided the title compoundas a white foam.

¹H NMR (400 MHz, CDCl₃) δ ppm 7.08-7.27 (4 H, m), 6.93-7.00 (2 H, m),6.65-6.87 (2 H, m), 5.50 (1 H, br, s), 4.55-4.70 (2 H, m), 3.55-3.68 (1H, m), 3.09-3.18 (2 H, m), 2.79 (1 H, d, J=15.1 Hz), 2.35-2.69 (2 H, m),1.74-1.94 (2 H, m), 1.53 (3 H, s), 1.47 (9 H, s.), 0.36-0.49 (1 H, m),0.23-0.35 (1 H, m), −0.34-−0.15 (1 H, m), −0.87-−0.71 (1 H, m); MS (ESI)m/z=645.0 [M+H]⁺, 643.0 [M−H]⁻.

Examples 268 and 269 were also prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 252, Step A) by procedures similar to the ones described inExample 267, substituting 2-methylpropane-2-sulfonamide in step A withthe appropriate amount of reagent listed in the table.

Example R Reagent used 268

ethanesulfonamide 269

cyclopropanesulfonamide

Example 2682-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(difluoromethyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.78 (br. s., 1 H)-0.22 (br. s., 1H) 0.31 (br. s., 1 H) 0.42 (br. s., 1 H) 1.38-1.49 (m, 3 H) 1.52 (s, 3H) 1.57-2.11 (br. s., 2 H) 2.40-2.52 (m., 2 H) 2.78 (d, J=15.41 Hz, 1 H)3.08-3.27 (m, 4 H) 3.42-4.02 (br. s., 2 H) 4.57-4.74 (m, 2 H) 6.80 (d,J=7.34 Hz, 1 H) 6.95 (s, 1 H) 7.08-7.18 (m, 2 H) 7.27 (m., 4 H); MassSpectrum (ESI) m/z=617 (M+1).

Example 2692-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(difluoromethyl)cyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.79 (br. s., 1 H)-0.23 (br. s., 1H) 0.31 (br. s., 1 H) 0.42 (br. s., 1 H) 1.12-1.36 (m, 3 H) 1.51 (s, 3H) 1.59-1.95 (m, 5 H) 2.44 (br. s., 2 H) 2.77 (d, J=15.41 Hz, 1 H)3.04-3.26 (m, 2H) 3.53 (m, 1 H) 4.48-4.70 (m, 2 H) 6.79 (d, J=7.34 Hz, 1H) 6.93 (s, 1 H) 7.07-7.18 (m, 2 H) 7.27 (m., 4 H); Mass Spectrum (ESI)m/z=629 (M+1).

Example 270143R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylicacid

Step A. (S)-Methyl2-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-hydroxypropanoate

To a solution of diisopropylamine (249 μL, 1.75 mmol) in THF (1.2 mL)was added 1.6 M n-BuLi in hexanes (984 μL, 1.57 mmol) slowly at −15° C.After 30 minutes, a solution of methyl2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(255 mg, 0.35 mmol; Example 263, Step B) in THF (1.2 mL) was addeddropwise to the LDA solution and the resulting solution was stirred at−15° C. for 30 min (the solution turned bright yellow). Then,formaldehyde in N₂ stream was carried over the reaction surface for 5min (formaldehyde was generated by cracking para-formaldehyde (105 mg,3.50 mmol) with heat gun) at −15° C. After being stirred at −15° C. for30 min, the reaction was allowed to warm to rt and stirred for 4 h. Thereaction was quenched (ice cold sat. NH₄Cl), extracted (2×EtOAc) andwashed (brine×3). The combined organic layers were dried (Na₂SO₄) andconcentrated under the reduced pressure. Purification of the residue bychromatography on silica gel (24 g SiO₂, 20% and 50% EtOAc/Hex) providedthe title compound as a colorless film.

Step B. Methyl2-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate

To a solution of (S)-methyl2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-hydroxypropanoate(132 mg, 0.173 mmol; Example 270, Step A) and triethylamine (97 μL, 0.69mmol) in DCM (2.2 mL) was added a solution of methanesulfonyl chloride(27 μL, 0.35 mmol) in DCM (2.2 mL) at 0° C. Then the reaction wasallowed to warm to rt and stirred for 3 h. The reaction was quenched(water), extracted (2×EtOAc) and washed (brine). The combined organiclayers were dried (Na₂SO₄) and concentrated under the reduced pressureto provide a crude mesylated compound, (S)-methyl2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)-3-(methylsulfonyloxy)propanoate.

To a solution of the crude mesylated compound from above in DCM (2.2 mL)was added DBU (78 μL, 0.52 mmol) and the resulting solution was stirredat rt for 1 h. The reaction was quenched (ice cold sat. NH₄Cl),extracted (2×EtOAc) and washed (brine). The combined organic layers weredried (Na₂SO₄) and concentrated under the reduced pressure. Purificationof the residue by chromatography on silica gel (12 g SiO₂, 10% and 20%EtOAc/Hex) provided the title compound as a colorless film.

Step C. Methyl1-((3R,5R,6S)-1-((S)-2-((tert-butyldiphenylsilyl)oxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate

To a suspension of trimethylsulfoxonium iodide (39 mg, 0.18 mmol) inDMSO (0.71 mL) was added a suspension of 60% sodium hydride in mineraloil (7.1 mg, 0.18 mmol). After being stirred 15 min, a solution ofmethyl2-((3R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acrylate(66 mg, 0.089 mmol; Example 270, Step B) in DMSO (0.71 mL) was added andthe mixture was stirred at rt for 3 h. The reaction was quenched (icecold sat. NH₄Cl), extracted (2×EtOAc), and washed (brine×3). Thecombined organic layers were dried (Na₂SO₄) and concentrated under thereduced pressure. Purification of the residue by chromatography onsilica gel (4 g SiO₂, 10% and 20% EtOAc/Hex) provided the title compoundas a colorless film.

Step D. Methyl1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate

To a solution of methyl143R,5R,6S)-1-((S)-2-(tert-butyldiphenylsilyloxy)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate(53 mg, 0.070 mmol; Example 270, Step C) in THF (0.70 mL) was added 1 MTBAF in THF (0.21 mL, 0.21 mmol) and the reaction was stirred at rtovernight. The reaction was quenched (sat. NH₄Cl), extracted (2×EtOAc),and washed (brine). The combined organic layers were dried (Na₂SO₄) andconcentrated under the reduced pressure. Purification of the residue bychromatography on silica gel (4 g SiO₂, 10%, 45%, and 55% EtOAc/Hex)provided the title compound as a white foam

Step E. Methyl1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate

The tile compound was prepared from methyl143R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate(35 mg, 0.068 mmol; Example 270, Step D) and cyclopropanesulfonamide (25mg, 0.20 mmol) by a procedure similar to the one described in Example202, Step C. Purification of the residue by chromatography on silica gel(4 g SiO₂, 45% and 60% EtOAc/Hex) provided the title compound as a paleyellow.

Step F.1-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylicacid

The title compound was prepared from methyl143R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopropanesulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)cyclopropanecarboxylate(27 mg, 0.043 mmol; Example 270, Step E) by a procedure similar to theone described in Example 263, Step E. Purification of the residue byreverse phase preparatory HPLC (Gemini™ Prep C₁₈ 5 μm column,Phenomenex, Torrance, Calif.; gradient elution of 45% to 70% MeCN inwater, where both solvents contain 0.1% TFA) provided the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.03-7.26 (6 H, m), 6.92-6.96 (1 H,m), 6.79 (1 H, d, J=7.0 Hz), 4.79 (1 H, d, J=10.6 Hz), 3.37-3.48 (1 H,m), 3.12-3.20 (1 H, m), 2.78 (1 H, dd, J=14.0, 2.2 Hz), 2.37-2.45 (1 H,m), 2.15-2.25 (1H, m), 1.80-1.88 (1 H, m), 1.38-1.50 (2 H, m), 1.45 (3H, s), 1.10-1.31 (7 H, m), 0.93-1.01 (2 H, m), 0.35-0.54 (2 H, m),−0.09-0.12 (1 H, m), −0.72-−0.23 (1 H, m); MS (ESI) m/z=605.0 [M+H]⁺,603.1 [M−H]⁻.

Example 271 (Intermediate)

A: N-(2-fluorophenyl)ethanesulfonamide

To a solution of ethanesulfonyl chloride (0.368 ml, 3.89 mmol) in DCM (1ml) and pyridine (1 ml) was added 2-fluoroaniline (0.360 ml, 3.89 mmol)at rt and the reaction was stirred at 50° C. for 5 hours. The reactionwas then stirred at rt overnight. The reaction was diluted with EtOAcand washed with H₂O and sat. NaCl solution. The organic layer was driedover Na₂SO₄ and concentrated. Purification of the residue by flashchromatography on silica gel (eluent: 0% to 35% EtOAc/hexane) providedthe title compound as a white solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.42 (t, J=8 Hz, 3 H), 3.15 (q, J=8Hz, 2 H), 6.48 (s, br, 1 H), 7.17 (m, 3H), 7.64 (m, 1 H).

In a similar fashion the following were prepared:

B: N-(phenyl)ethanesulfonamide: ¹H NMR (400 MHz, chloroform-d) δ ppm1.38 (t, J=8 Hz, 3H), 3.14-3.20 (q, J=8 Hz, 2H), 7.15-7.17 (m, 1H),7.29-7.36 (m, 4H).

C: N-(3-fluorophenyl)ethanesulfonamide: ¹H NMR (400 MHz, chloroform-d) δppm 1.42 (t, J=8 Hz, 3H), 3.17-3.23 (q, J=8 Hz, 2H), 6.78 (s, br, 1H),6.89 (m, 1H), 6.99 (m, 1H), 7.04 (m, 1H), 7.77 (m, 1H).

D: N-(pyridin-3-yl)methanesulfonamide: ¹H NMR (400 MHz, methanol-d4) δppm 3.05 (s, 3H), 7.43-7.46 (dd, J=4, 8 Hz, 1H), 7.78-7.81 (dd, J=2, 4Hz, 1H), 8.33 (d, J=4Hz, 1H), 8.45 (s, 1H). Mass Spectrum (ESI)m/z=173.2 (M+1).

E: N-(phenyl)cyclopropanesulfonamide: ¹H NMR (400 MHz, CHLOROFORM-d) δppm 0.96-1.00 (m, 2H), 1.18-1.22 (m, 2H), 2.48-2.55 (m, 1H), 7.20-7.22(m, 1H), 7.28-7.30 (m, 2H), 7.37-7.39 (m, 2H).

F: propane-1-sulfonamide [CAS no. 24243-71-8]

A stream of anhydrous ammonia was bubbled into a solution ofpropane-1-sulfonyl chloride (7.3 g, 51.2 mmol) in anhydrous THF (100 ml)on ice bath. Bubbling was continued for 1 hour during which a lot ofwhite solid precipitated. The reaction was then stirred at rt for 2days. The reaction mixture was diluted with EtOAc, washed with H₂O andsat. NaCl, dried with Na₂SO₄, and then concentrated. Purification of thecrude using flash chromatography on silica gel (eluted with 0% to 35%EtOAc/hexane) gave the title compound as a white solid (3.0 g, 47.6%).

¹H NMR (400 MHz, chloroform-d) δ ppm −1.10 (t, J=8 Hz, 3H), 1.91 (m,2H), 3.11 (m, 2H), 4.94 (s, 2H).

G: Cyclobutanesulfonamide [CAS no. 445305-91-9]

A stream of anhydrous ammonia was bubbled for 30 min through a stirredsolution of cyclobutanesulfonyl chloride (5 g, 32.3 mmol; HandeSciences) in dry THF (100 mL) at 0° C., causing formation of a whiteprecipitate. The suspension was warmed to ambient temperature andstirred overnight. The mixture was filtered and the filter cake wascopiously washed with ethyl acetate. The filtrate was concentrated underreduced pressure, redissolved in ca. 150 mL EtOAc, and washed 3× withbrine. Organics were dried over sodium sulfate, filtered, andconcentrated in vacuo to give a white, partially crystalline residuethat was triturated with hexanes and dried under high vacuum to givecyclobutanesulfonamide as a fluffy white solid, 1.8 g (41% yield).

¹H NMR (400 MHz, CHLOROFORM-d) δ 1.96-2.10 (m, 2 H), 2.30-2.43 (m, 2 H),2.43-2.59 (m, 2 H), 3.72-4.01 (m, 1 H), 4.70 (br. s., 2 H).

Example 2722-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(2-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(2-fluorophenyl)ethanesulfonamide

To a mixture of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 252, Step A, 70 mg, 0.153 mmol) andN-(2-fluorophenyl)ethanesulfonamide (93 mg, 0.458 mmol) in toluene (1ml) was added cyanomethylenetri-n-butylphosphorane (0.111 ml, 0.458mmol) at rt and the mixture was flushed with N₂ for about 20 minutes.The reaction was sealed and heated to 70° C. overnight. The reactionmixture was purified by flash chromatography on silica gel (eluent: 0%to 35% EtOAc/hexanes) to provide the title compound as a solid.

¹H NMR (400 MHz, methanol-d4) ppm −1.25 (s, br, 1 H), −0.64 (s, br, 1H), 0.00 (s, br, 1 H), 0.16 (s, br, 1 H), 0.73 (m, 1 H), 0.92 (s, 3 H),1.19 (m, 4 H), 1.48 (m, 1 H), 1.66 (m, 1 H), 2.00 (m, 2 H), 2.24 (m, 1H), 2.52 (m, 1 H), 2.97 (m, 2 H), 3.71 (s, br, 1 H), 4.56 (d, J=12 Hz, 1H), 5.01 (m, 1 H), 5.05 (s, 1 H), 5.73 (m, 1 H), 6.83-6.91 (m, 3 H),7.03-7.16 (m, 7 H), 7.28 (m, 1 H), 7.45 (m, 1 H).

Mass Spectrum (ESI) m/z=643.2 (M+1)

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(2-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(2-fluorophenyl)ethanesulfonamide(Example 272, Step A, 72 mg, 0.112 mmol) in THF (0.600 ml), water (0.396ml) and BuOH (0.3 ml) was added 4-methylmorpholine 4-oxide (45.9 mg,0.392 mmol) followed by osmium(VIII) oxide (0.037 ml, 2.80 μmol). Thereaction was stirred at rt overnight. Sodium periodate (71.8 mg, 0.336mmol) was added and the reaction was stirred at rt for 2 hours. To thisreaction was added 1.25M KH₂PO₄ (0.80 ml), 1 M of 2-methylbut-2-enesolution in THF (2.24 ml, 4.47 mmol) and sodium chlorite (50.6 mg, 0.56mmol) and the reaction was stirred at rt for 2 hours. Upon the end ofthe reaction 0.8 ml of 1 M aq. NaS₂O₃ aq. was added and the reaction wasstirred at rt for 10 minutes followed by adding 0.8 ml of 1 M aq. KHSO₄.

The reaction was then diluted with EtOAc and washed with H₂O and sat.NaCl. The organic layer was dried with Na₂SO₄ and concentrated. Theproduct was purified by reversed phase preparatory HPLC (eluents: 40-85%of acetonitile in water with 0.1% of TFA gradient on Gemini™ Prep C₁₈ 5um column, Phenomenex, Torrance, Calif.) to give the title compound as awhite solid.

¹H NMR (400 MHz, methanol-d₄) ppm −1.28 (s, br, 1H), −0.63 (s, br, 1H),0.00 (s, br, 1H), 0.17 (s, br, 1H), 1.07 (s, 3H), 1.20 (t, J=4Hz, 3H),1.51-1.55 (m, 1H), 1.91-1.95 (dd, J=4 Hz, 16 Hz, 1H), 2.05 (s, br, 1H),2.11 (t, J=12 Hz, 1H), 2.49-2.53 (d, J=16 Hz, 1H), 2.79-2.83 (d, J=16Hz, 1H), 2.98 (s, br, 2H), 3.27 (m, 1H), 3.71 (s, br, 1H), 4.62 (s, br,2H), 6.87 (d, J=8 Hz, 2H), 6.92 (s, 1H), 7.03-7.18 (m, 7H), 7.29 (m,1H), 7.49 (s, br, 1H).

Mass Spectrum (ESI) m/z=661.2 (M+1)

Examples 273-289, were prepared in a similar fashion to example 272.Using the corresponding sulfonamide and the alcohol of Example 252, StepA, allyl sulfonamides were formed in Step A and converted to thecorresponding carboxylic acids in Step B.

Example Reagent used Source or CAS# 272N-(2-fluorophenyl)ethanesulfonamide Example 271A 273N-(2-fluorophenyl)methanesulfonamide [98611-90-6] 274N-(phenyl)cyclopropanesulfonamide Example 271E 275N-(phenyl)ethanesulfonamide Example 271B 276 ethanesulfonamide [1520-70-3] 277 N-(3-fluorophenyl)ethanesulfonamide Example 271C 278N-(2-cyanophenyl)methanesulfonamide [50790-29-9] 279propane-1-sulfonamide Example 271F 280 N-(phenyl)methanesulfonamide [1197-22-4] 281 N-(3-cyanophenyl)methanesulfonamide [50790-30-2] 282N-(pyridin-3-yl)methanesulfonamide Example 271D 283 N-(thiophen-2-BBB-SCI ylmethyl)methanesulfonamide 3B3-026467, Libertyville, IL 284N-(3-MeOPhenylmethyl)- methanesulfonamide 285 alpha-toluenesulfonamide [4563-33-1] 286 pyridin-2-ylmethanesulfonamide Princeton PBMR006092,Monmouth Junction NJ 287 pyridin-3-ylmethanesulfonamide PrincetonPBMR006093, Monmouth Junction NJ 288 N-(pyridin-2-yl)methanesulfonamide[74351-44-3] 289 methanesulfonamide [3144-09-0]

Example 2732-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(2-fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(2-fluorophenyl)methanesulfonamide

¹H NMR (400 MHz, methanol-d4) δ ppm −1.20 (s, br, 1H), −0.63 (s, br,1H), 0.00 (s, br, 1H), 0.13 (s, br, 1H), 0.88 (s, 3H), 1.48 (m, 1H),1.64 (d, J=12 Hz, 1H), 1.94-1.99 (s, 2H), 2.19 (d, J=8 Hz, 2H), 2.72 (s,3H), 2.99 (m, 1H), 3.54 (s, br, 1H), 4.50 (d, J=8 Hz, 1H), 4.59 (s, br,1H), 4.96-5.01 (m, 2H), 5.65 (m, 1H), 6.70 (s, br, 2H), 6.80 (s, br,2H), 6.96-7.08 (m, 6H), 7.19 (m, 1H), 7.27 (m, 1H).

Mass Spectrum (ESI) m/z=629.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(2-fluorophenyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.27 (s, br, 1H), −0.58 (s, br,1H), 0.00 (s, br, 1H), 0.18 (s, br, 1H), 1.03 (s, 3H), 1.07-1.04 (m,1H), 1.50 (m, 1H), 1.90-1.94 (dd, J=4, 12 Hz, 1H), 2.08 (t, J=16 Hz,1H), 2.47 (d, J=16 Hz, 1H), 2.78 (d, J=16 Hz, 1H), 2.81 (s, 3H), 3.26(m, 1H), 3.67 (s, br, 1H), 4.57 (d, J=12 Hz, 1H), 6.84 (d, J=8 Hz, 2H),6.90 (s, 1H), 7.03 (m, 4H), 7.16 (m, 2H), 7.29 (m, 1H), 7.31 (m, 1H).

Mass Spectrum (ESI) m/z=647.0 (M+1).

Example 2742-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-phenylcyclopropanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.24 (s, br, 1H), −0.56 (s, br,1H), 0.00 (s, br, 1H) 0.20 (s, br, 1H), 0.69-0.78 (m, 4H), 0.92 (s, br,3H), 1.55 (s, br, 1H), 1.62-1.66 (dd, J=4, 12 Hz, 1H), 1.93-2.00 (m,2H), 2.36-2.45 (m, 2H), 2.51-2.57 (m, 1H), 3.12-3.19 (m, 1H), 3.81 (s,br, 1H), 4.42-4.45 (d, br, J=12 Hz, 1H), 4.76 (s, br, 1H), 5.00-5.05 (t,J=8 Hz, 1H), 5.09 (s, 1H), 5.70-5.79 (m, 1H), 6.79 (m, 2H), 6.92 (s,1H), 7.04 (m, 4H), 7.18-7.30 (m, 2H), 7.72 (m, 2H), 7.44 (d, J=8 Hz).

Mass Spectrum (ESI) m/z=637.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylcyclopropanesulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.28 (s, br, 1H), −0.54 (s, br,1H), 0.00 (s, br, 1H), 0.20 (s, br, 1H), 0.70-0.78 (m, 5H), 1.06 (s,3H), 1.53 (s, br, 1H), 1.91-2.07 (m, 3H), 2.37 (s, br, 1H), 2.48 (d,J=12 Hz, 1H), 2.78 (d, J=12 Hz, 1H), 3.24 (m, 1H), 3.80 (s, br, 1H),4.43 (d, J=12 Hz, 1H), 6.82 (d, J=8 Hz, 2H), 6.92 (s, 1H), 7.05 (m, 4H),7.22 (t, J=8 Hz, 2H), 7.33 (t, J=8 Hz, 2H), 7.44 (d, J=8 Hz, 2H).

Mass Spectrum (ESI) m/z=655.2 (M+1).

Example 2752-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-phenylethanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.23 (s, br, 1H), −0.56 (s, br,1H), 0.00 (s, br, 1H), 0.19 (s, br, 1H), 0.92 (s, 3H), 1.13 (t, J=8 Hz,3H), 1.55 (s, br, 2H), 1.63 (dd, J=4, 8 Hz, 1H), 1.96 (m, 2H), 2.45 (m,1H), 2.53 (m, 1H), 2.90 (m, 2H), 3.17 (m, 1H), 3.79 (s, br, 1H), 4.42(d, J=12 Hz, 1H), 4.81 (s, br, 1H), 5.00 (m, 1H), 5.09 (s, 1H), 5.72 (m,1H), 6.79 (m, 2H), 6.94 (s, 1H), 7.02 (m, 4H), 7.19 (m, 2H), 7.32 (t,J=8 Hz, 2H), 7.47 (d, J=8 Hz, 2H).

Mass Spectrum (ESI) m/z=625.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −1.26 (s, br, 1H), −0.55 (s, br,1H), 0.19 (s, br, 1H), 1.06 (s, 3H), 1.13 (t, J=8 Hz, 3H), 1.51 (s, br,1H), 1.88 (dd, J=4, 8 Hz, 1H), 2.00 (s, br, 1H), 2.03 (t, J=12 Hz, 1H),2.48 (d, J=12 Hz, 1H), 2.78 (d, J=12 Hz, 1H), 2.90 (m, 2H), 3.23 (m,1H), 3.77 (d, J=12 Hz, 1H), 4.46 (d, J=8 Hz, 1H), 4.76 (s, br, 1H),

Mass Spectrum (ESI) m/z=643.2 (M+1).

Example 2762-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)ethanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.06 (s, br, 1H), −0.98 (m, 1H),−0.02 (m, 1H), 0.14 (m, 1H), 1.08 (s, 3H), 1.14 (t, J=4Hz, 3H), 1.39 (m,1H), 1.59 (dd, J=4, 12 Hz, 1H), 2.05 (m, 1H), 2.10 (t, J=16 Hz, 1H),2.42 (m, 1H), 2.50 (m, 1H), 2.89 (m, 3H), 3.12 (m, 1H), 3.74 (m, 1H),4.68 (d, J=12 Hz, 1H), 4.96-5.06 (m, 2H), 5.71 (m, 1H), 6.79 (m, 2H),6.87 (s, 1H), 6.93 (m, 3H), 7.06 (m, 2H).

Mass Spectrum (ESI) m/z=549.0 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.06 (s, br, 1H), −0.47 (m, 1H),−0.02 (m, 1H), 0.14 (m, 1H), 1.13 (t, J=8 Hz, 3H), 1.22 (s, 3H), 1.06(s, br, 1H), 1.89 (dd, J=4, 12 Hz, 1H), 2.08 (s, 1H), 2.15 (t, J=16 Hz,1H), 2.46 (d, J=12 Hz, 1H), 2.80 (d, J=12 Hz, 1H), 3.07 (m, 3H), 3.19(m, 1H), 3.65 (m, 1H), 4.69 (d, J=8 Hz, 1H), 6.81 (m, 2H), 6.92 (s, 1H),6.87 (m, 3H), 7.05 (s, br, 2H).

Mass Spectrum (ESI) m/z=567.0 (M+1).

Example 2772-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(3-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(3-fluorophenyl)ethanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.20 (s, br, 1H), −0.56 (s, br,1H), 0.00 (s, br, 1H), 0.19 (s, br, 1H), 0.89 (s, 3H), 1.08 (m, 3H),1.53 (s, br, 1H), 1.62 (dd, J=4, 12 Hz, 1H), 1.90 (t, J=12 Hz, 1H), 1.95(m, 1H), 2.38 (m, 1H), 2.52 (m, 1H), 2.86-2.96 (m, 2H), 3.11-3.17 (m,1H), 3.76 (d, J=12 Hz, 1H), 4.77 (s, br, 1H), 5.00 (t, J=8 Hz, 1H), 5.06(s, 1H), 5.72 (m, 1H), 6.77 (m, 2H), 6.89 (m, 3H), 7.00 (m, 4H), 7.28(m, 3H).

Mass Spectrum (ESI) m/z=643.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(3-fluorophenyl)ethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −1.06 (s, br, 1H), −0.39 (s, br,1H), 0.16 (1H), 0.35 (s, br, 1H), 1.21 (s, br, 3H), 1.28 (t, J=4Hz, 3H),1.67 (s, br, 1H), 2.04-2.18 (m, 3H), 2.63 (d, J=12 Hz, 1H), 2.93 (d,J=12 Hz, 1H), 3.09 (s, br, 2H), 3.39 (m, 1H), 3.92 (m, 1H), 3.92 (s, br,1H), 4.56 (s, br, 1H), 6.96 (m, 2H), 7.06 (m, 3H), 7.17 (m, 4H), 7.45(m, 3H).

Mass Spectrum (ESI) m/z=661.2 (M+1)

Example 2782-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(2-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(2-cyanophenyl)methanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.22 (s, br, 1H), −0.47 (s, br,1H), 0.00 (s, br, 1H), 0.19 (s, br, 1H), 0.91 (s, br, 1H), 1.45 (m, 1H),1.67 (d, J=12 Hz, 1H), 1.97 (m, 1H), 2.10 (s, br, 1H), 2.42 (m, 1H),2.52 (m, 1H), 2.87 (s, 3H), 3.15-3.18 (m, 2H), 3.91 (s, br, 1H), 4.47(s, br, 1H), 4.99 (m, 1H), 5.07 (s, 1H), 5.71 (m, 1H), 6.79 (s, br, 2H),6.89 (s, 1H), 6.96 (s, br, 3H), 7.05 (s, br, 2H), 7.40 (m, 1H), 7.62 (m,2H), 7.72 (s, br, 1H).

Mass Spectrum (ESI) m/z=636.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(2-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.12 (s, br, 1H), −0.31 (s, br,1H), 0.15 (s, br, 1H), 0.35 (s, br, 1H), 1.20 (s, 3H), 1.29 (m, 1H),1.62 (s, br, 1H), 2.06 (d, 1H), 2.24 (t, J=12 Hz, 1H), 2.27 (s, br, 1H),2.60 (d, J=12 Hz, 1H), 2.93 (d, J=12 Hz, 1H), 3.02 (s, 3H), 3.41 (m,1H), 4.01 (s, br, 1H), 4.68 (s, br, 1H), 6.98 (d, J=8 Hz, 2H), 7.06 (s,1H), 7.12 (m, 3H), 7.21 (s, br, 2H), 7.57 (m, 1H), 7.79 (m, 2H), 7.88(s, br, 1H).

Mass Spectrum (ESI) m/z=654.0 (M+1).

Example 2792-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(propylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)propane-1-sulfonamide

Crude product used directly in Step B.

Mass Spectrum (ESI) m/z=563.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(propylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.85 (s, br, 1H), −0.25 (s, br,1H), 0.22 (s, br, 1H), 0.35 (m, 1H), 1.08 (t, J=4Hz, 3H), 1.43 (s, 3H),1.55 (s, br, 1H), 1.84 (m, 2H), 2.10 (dd, J=4, 8 Hz, 1H), 2.30 (s, br,1H), 2.36 (t, J=12 Hz, 1H), 2.67 (d, J=16 Hz, 1H), 2.98 (d, J=16 Hz,1H), 3.05 (m, 3H), 3.41 (m, 1H), 3.88 (m, 1H), 4.92 (d, J=8 Hz, 1H),7.02 (m, 2H), 7.08 (s, 1H), 7.14 (m, 3H), 7.26 (s, br, 2H).

Mass Spectrum (ESI) m/z=581.2 (M+1).

Example 2802-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-phenylmethanesulfonamide

Mass Spectrum (ESI) m/z=611.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.26 (s, br, 1H), −0.51 (s, br,1H), 0.00 (s, br, 1H), 0.20 (s, br, 1H), 1.03 (s, 3H), 1.54 (s, br, 1H),1.80-2.04 (m, 3H), 2.47 (d, J=16 Hz, 1H), 2.73 (s, 3H), 2.78 (d, J=16Hz, 1H), 3.18 (m, 1H), 3.75 (s, br, 1H), 4.42 (s, J=12 Hz, 1H), 6.81 (m,2H), 6.91 (s, 1H), 7.04 (m, 4H), 7.24 (m, 2H), 7.35 (m, 2H), 7.43 (m,2H).

Mass Spectrum (ESI) m/z=629.0 (M+1).

Example 2812-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(3-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(3-cyanophenyl)methanesulfonamide

¹H NMR (400 MHz, chloroform-d₁) δ ppm −1.17 (s, br, 1H), −0.59 (s, br,1H), 0.00 (s, br, 1H), 0.12 (s, br, 1H), 0.74 (s, 3H), 1.36 (m, 1H),1.44-1.60 (m, 2H), 1.68 (t, J=12 Hz, 1H), 2.36 (d, J=8 Hz, 2H), 2.60 (s,3H), 2.95 (m, 1H), 4.33 (s, br, 1H), 4.70 (s, br, 1H), 4.92 (s, 1H),4.95 (d, J=4Hz, 1H), 5.58 (m, 1H), 6.62 (s, br, 2H), 6.69 (s, br, 2H),6.95 (m, 4H), 7.33-7.40 (m, 2H), 7.50 (s, 1H), 7.54 (s, 1H).

Mass Spectrum (ESI) m/z=636.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(N-(3-cyanophenyl)methylsulfonamido)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.21 (s, br, 1H), −0.55 (s, br,1H), 0.00 (s, br, 1H), 0.18 (s, br, 1H), 0.95 (s, 3H), 1.45 (s, br, 1H),1.89 (d, J=8 Hz, 2H), 1.99 (s, br, 1H), 2.42 (d, J=12 Hz, 1H), 2.72 (s,3H), 2.75 (d, J=12 Hz, 1H), 3.19 (m, 1H), 3.73 (s, br, 1H), 4.37 (s, br,1H), 6.80 (s, 3H), 6.96-7.05 (m, 5H), 7.45-7.49 (m, 1H), 7.52 (d, J=8Hz, 1H), 7.70 (s, br, 1H), 7.77 (s, br, 1H).

Mass Spectrum (ESI) m/z=654.1 (M+1).

Example 2822-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(pyridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(pyridin-3-yl)methanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.18 (s, br, 1H), −0.57 (s, br,1H), 0.00 (s, br, 1H), 0.17 (s, br, 1H), 0.78 (s, 3H), 1.45 (s, br, 1H),1.60 (m, 1H), 1.86 (m, 1H), 2.00 (s, br, 1H), 2.38 (m, 1H), 2.47 (m,1H), 2.74 (s, 3H), 3.14 (m, 2H), 3.76 (s, br, 1H), 4.41 (s, br, 1H),4.95-5.00 (m, 2H), 5.67 (m, 1H), 6.78-6.82 (m, 3H), 6.97-7.04 (m, 5H),7.36 (m, 1H), 7.84 (s, br, 1H), 8.31 (m, 11H), 8.60 (s, br, 1H).

Mass Spectrum (ESI) m/z=612.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(pyridin-3-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.19 (s, br, 1H), −0.55 (s, br,1H), 0.00 (s, br, 1H), 0.16 (s, br, 1H), 0.95 (m, 4H), 1.34 (s, br, 1H),1.90 (m, 2H), 2.42 (d, J=12 Hz, 1H), 2.72 (s, J=12 Hz, 1H), 2.75 (s,3H), 3.20 (s, br, 1H), 3.38 (s, br, 1H), 4.43 (s, br, 2H), 6.83 (m, 3H),6.98 (m, 5H), 7.52 (s, br, 1H), 8.04 (s, br, 1H), 8.39 (s 1H), 0.68 (s,1H).

Mass Spectrum (ESI) m/z=630.1 (M+1).

Example 2832-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(thiophen-2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(thiophen-2-ylmethyl)methanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm (representative signals) 5.30-5.35(m, 1H), 5.40 (s, 1H), 6.06 (m, 1H). Mass Spectrum (ESI) m/z=631.2(M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(thiophen-2-ylmethyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.12 (s, br, 1H), −0.59 (s, br,1H), 0.00 (s, br, 1H), 0.14 (s, br, 1H), 1.21 (s, 3H), 1.49 (s, br, 1H),1.80 (d, J=12 Hz, 1H), 1.94 (s, br, 1H), 2.19 (t, J=12 Hz, 1H), 2.47 (d,J=12 Hz, 1H), 2.58 (s, 3H), 2.73 (d, J=12 Hz, 1H), 3.01 (s, br, 1H),3.14 (m, 1H), 2.47 (s, br, 1H), 4.53-4.47 (m, 3H), 6.76 (m, 3H), 6.85(s, 2H), 6.95-7.02 (m, 5H), 7.11 (d, J=4Hz, 1H).

Mass Spectrum (ESI) m/z=649.0 (M+1).

Example 2842-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(3-methoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(3-methoxybenzyl)methanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.07 (s, br, 1H), −0.43 (s, br,1H), 0.13 (s, br, 1H), 0.28 (s, br, 1H), 1.25 (s, 3H), 1.68 (s, br, 2H),1.90 (s, br, 1H), 2.37 (s, br, 1H), 2.62 (m, 2H), 2.83 (s, 3H), 3.19 (m,2H), 3.78 (s, 3H), 4.21 (s, 2H), 4.50 (s, br, 2H), 5.14-5.22 (m, 2H),5.87 (m, 1H), 6.82-6.93 (m, 3H), 6.94 (m, 4H), 7.17-7.27 (m, 5H).

Mass Spectrum (ESI) m/z=655.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(3-methoxybenzyl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.23 (s, br, 1H), −0.55 (s, br,1H), 0.00 (s, br, 1H), 0.16 (s, br, 1H), 1.28 (s, 3H), 1.81 (m, 2H),2.31 (m, 1H), 2.54 (d, J=12 Hz, 1H), 2.77 (m, 4H), 3.10 (s, br, 1H),3.16 (m, 1H), 3.59 (s, 5H), 3.98 (s, br, 1H), 4.45 (s, br, 2H),6.73-6.78 (m, 3H), 6.85 (m, 2H), 6.94 (s, 1H), 7.06 (m, 5H).

Mass Spectrum (ESI) m/z=673.0 (M+1).

Example 2852-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-1-phenylmethanesulfonamide

¹H NMR (400 MHz, chloroform-d₁) δ ppm −0.36 (s, br, 1H), 0.00 (s, br,1H), 0.48 (s, br, 2H), 1.28 (s, br, 1H), 1.32 (s, 3H), 2.00 (m, 1H),2.16 (m, 2H), 2.72 (m, 2H), 2.89 (s, br, 2H), 3.23 (m, 1H), 3.26 (s,1H), 4.84 (d, J=12 Hz, 1H), 5.11 (s, br, 1H), 5.26 (s, 1H), 5.29 (d,J=4Hz, 1H), 5.93 (m, 1H), 6.89 (d, J=8 Hz, 1H), 7.05 (s, 1H), 7.10 (s,br, 1H), 7.22 (m, 2H), 7.29 (d, J=4Hz, 2H), 7.48 (m, 5H).

Mass Spectrum (ESI) m/z=611.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(phenylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, chloroform-d₁) δ ppm −0.92 (s, br, 1H), −0.35 (s, br,1H), 0.15 (s, br, 1H), 0.29 (m, 1H), 1.42 (s, 3H), 1.48 (s, 1H), 2.05(dd, J=4, 12 Hz, 1H), 2.20 (s, 1H), 2.33 (t, J=16 Hz, 1H), 2.65 (d, J=12Hz, 1H), 2.84 (dd, J=4, 12 Hz, 1H), 2.96 (d, J=12 Hz, 1H), 3.38 (m, 1H),3.72 (m, 1H), 4.37 (s, 2H), 4.97 (m, 1H), 7.01 (d, J=4Hz, 2H), 7.06 (s,1H), 7.13 (m, 3H), 7.24 (s, br, 2H), 7.38-7.46 (m, 5H).

Mass Spectrum (ESI) m/z=629.2 (M+1).

Example 2862-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyridin-2-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-1-(pyridin-2-yl)methanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.08 (s, br, 1H), −0.49 (s, br,1H), 0.02 (s, br, 1H), 0.12 (s, br, 1H), 1.09 (s, 3H), 1.36 (s, br, 1H),1.63 (dd, J=4, 12 Hz, 1H), 1.93 (s, br, 1H), 2.08 (t, J=12 Hz, 1H), 2.43(m, 1H), 2.53 (m, 1H), 2.83 (m, 1H), 3.66 (m, 1H), 4.36 (s, 2H), 4.39(s, br, 1H), 4.64 (m, 1H), 4.98-5.07 (m, 2H), 5.72 (m, 1H), 6.79 (m,2H), 6.87 (s, 1H), 6.94 (m, 3H), 7.10 (s, br, 2H), 7.24 (m, 1H), 7.42(d, J=8 Hz, 1H), 7.70 (m, 1H), 8.40 (m, 1H).

Mass Spectrum (ESI) m/z=612.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyridin-2-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.07 (s, br, 1H), −0.47 (s, br,1H), 0.00 (s, br, 1H), 0.16 (s, br, 1H), 1.20 (s, 3H), 1.35 (s, br, 1H),1.87 (dd, J=4, 8 Hz, 1H), 2.10 (m, 2H), 2.45 (d, J=12 Hz, 1H), 2.75 (d,J=12 Hz, 1H), 2.84 (m, 1H), 3.59 (m, 1H), 4.43 (s, 2H), 4.61 (m, 1H),6.76 (m, 2H), 6.84 (s, 1H), 6.91 (m, 3H), 7.05 (s, br, 2H), 7.45 (m,1H), 7.57 (d, J=8 Hz, 1H), 7.92 (t, J=8 Hz, 1H), 8.47 (m, 1H).

Mass Spectrum (ESI) m/z=630.1 (M+1).

Example 2872-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyridin-3-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-1-(pyridin-3-yl)methanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.06 (s, br, 1H), −0.48 (s, br,1H), 0.02 (s, br, 1H), 0.15 (s, br, 1H), 1.08 (s, 3H), 1.37 (s, br, 1H),1.61 (dd, J=4, 8 Hz, 1H), 1.99 (s, br, 1H), 2.08 (t, J=16 Hz, 1H), 2.43(m, 1H), 2.50 (m, 1H), 2.78 (m, 1H), 3.14 (m, 1H), 3.69 (s, br, 1H),4.26 (s, 2H), 4.63 (m, 1H), 4.97-5.05 (m, 2H), 5.71 (m, 1H), 6.78 (m,2H), 6.86 (s, 1H), 6.93 (m, 3H), 7.10 (s, br, 2H), 7.28 (m, 1H), 7.75(m, 1H), 8.36 (m, 1H), 8.41 (s, 1H).

Mass Spectrum (ESI) m/z=612.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyridin-3-ylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.59 (s, br, 1H), 0.00 (s, br, 1H),0.47 (s, br, 1H), 0.61 (s, br, 1H), 1.65 (s, 3H), 1.81 (s, br, 1H), 2.33(m, 1H), 2.55 (m, 2H), 2.91 (d, J=12 Hz, 1H), 3.21 (d, J=12 Hz, 1H),3.32 (m, 1H), 4.13 (s, br, 1H), 4.86 (s, 2H), 5.07 (m, 1H), 7.21 (m,2H), 7.30 (s, 1H), 7.36 (m, 3H), 7.49 (s, 2H), 8.15 (m, 1H), 8.69 (m,1H), 9.02 (m, 1H), 9.10 (s, 1H).

Mass Spectrum (ESI) m/z=630.1 (M+1).

Example 2882-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(pyridin-2-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-(pyridin-2-yl)methanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.75 (s, br, 1H), 0.00 (s, br, 1H),0.45 (s, br, 1H), 0.60 (s, br, 1H), 1.52 (s, 3H), 1.94-2.03 (m, 3H),2.83-2.95 (m, 2H), 3.08 (s, 3H), 3.12 (s, br, 1H), 3.48 (m, 1H), 3.87(s, br, 1H), 4.78 (s, br, 1H), 4.94 (s, br, 1H), 5.39-5.50 (m, 2H), 6.11(m, 1H), 6.83 (s, br, 1H), 6.94 (s, br, 1H), 7.14 (m, 1H), 7.32 (m, 3H),7.39 (s, br, 1H), 7.50 (s, br, 2H), 7.85 (m, 1H), 7.99 (m, 1H), 8.14 (s,br, 1H).

Mass Spectrum (ESI) m/z=612.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-(pyridin-2-yl)methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −0.75 (s, br, 1H), 0.00 (s, br, 1H),0.47 (s, br, 1H), 0.60 (s, br, 1H), 1.68 (s, 3H), 2.02 (s, br, 2H), 2.30(m, 1H), 2.94 (d, J=12 Hz, 1H), 3.11 (s, 3H), 3.19 (d, J=12 Hz, 1H),3.19 (s, br, 1H), 3.62 (m, 1H), 3.99 (s, br, 1H), 4.79 (s, br, 1H), 4.93(s, br, 1H), 6.92 (s, br, 2H), 7.00 (s, br, 1H), 7.15 (s, br, 1H), 7.35(m, 2H), 7.51 (s, br, 3H), 7.87 (s, br, 1H), 8.03 (d, J=4Hz, 1H), 8.15(s, br, 1H).

Mass Spectrum (ESI) m/z=630.1 (M+1).

Example 2892-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)methanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.87 (s, br, 1H), −0.24 (m, 1H),0.22 (m, 1H), 0.38 (m, 1H), 0.90 (m, 1H), 1.28 (s, 3H), 1.58 (m, 2H),1.84 (dd, J=4, 12 Hz, 1H), 2.13 (m, 1H), 2.27 (t, J=16 Hz, 1H), 2.63(dd, J=8, 16 Hz, 1H), 2.70 (dd, J=8, 16 Hz, 1H), 2.97 (s, 3H), 3.13 (m,1H), 3.90 (m, 1H), 2.42 (s, br, 1H), 5.17-5.27 (m, 2H), 5.92 (m, 1H),6.98 (m, 2H), 7.06 (s, 1H), 7.14 (m, 3H), 7.27 (m, 2H).

Mass Spectrum (ESI) m/z=535.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −1.07 (s, br, 1H), −0.45 (s, br,1H), 0.01 (s, br, 1H), 0.13 (m, br, 1H), 1.21 (s, 3H), 1.33 (s, br, 1H),1.89 (dd, J=4, 12 Hz, 1H), 2.11 (t, J=12 Hz, 1H), 2.15 (s, br, 1H), 2.45(d, J=16 Hz, 1H), 2.75 (s, 3H), 2.76 (d, J=16 Hz, 1H), 2.89 (m, 1H),3.18 (m, 1H), 3.62 (m, 1H), 4.67 (d, 1H), 6.79 (m, 2H), 6.85 (s, 1H),6.93 (m, 3H), 7.04 (s, br, 2H).

Mass Spectrum (ESI) m/z=553.2 (M+1).

Example 2902-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-ethylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-ethylmethanesulfonamide

To a solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)methanesulfonamide(Example 289, Step A, 86 mg, 0.161 mmol) in DMF (1.5 ml) was addedsodium hydride (16.06 mg, 0.401 mmol) at rt and the reaction was stirredat rt for 30 minutes. To this reaction was added iodoethane (0.058 mL,0.723 mmol) and the reaction was stirred at rt for 2 hours. The reactionwas diluted with EtOAc, washed with water and sat. NaCl, dried withNa₂SO₄ and then concentrated. The crude was used on next reaction.

Mass Spectrum (ESI) m/z=563.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-ethylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared using similar procedures as describedfor Example 272, Step B.

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.67 (s, br, 1H), −0.27 (s, br,1H), 0.30 (s, br, 1H), 0.40 (s, br, 1H), 1.18 (t, J=8 Hz, 3H), 1.41 (s,3H), 1.71 (s, br, 1H), 2.07 (dd, J=4, 12 Hz, 1H), 2.24 (s, br, 1H), 2.36(t, J=12 Hz, 1H), 2.68 (d, J=16 Hz, 1H), 2.92 (s, 3H), 2.96 (d, J=16 Hz,1H), 3.25 (s, br, 1H), 3.27 (m, 1H), 3.37 (m, 2H), 4.28 (s, br, 1H),4.81 (s, br, 1H), 6.98 (m, 2H), 7.04 (s, 1H), 7.14 (m, 3H), 7.27 (s, br,2H).

Mass Spectrum (ESI) m/z=581.2 (M+1).

Example 2912-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-isopropylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)-N-isopropylmethanesulfonamide

This compound was prepared using similar procedures as described forExample 290, Step A.

Mass Spectrum (ESI) m/z=577.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-isopropylmethylsulfonamido)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

This compound was prepared using similar procedures as described forExample 272 Step B.

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.43 (s, br, 1H), 0.00 (s, br, 1H),0.51 (s, br, 1H), 0.62 (s, br, 1H), 1.36 (s, br, 3H), 1.45 (s, br, 3H),1.62 (s, br, 3H), 1.97 (s, br, 1H), 2.24 (d, br, 1H), 2.54 (d, br, 2H),2.90 (d, J=12 Hz, 1H), 3.12 (s, br, 3H), 3.16 (d, J=12 Hz, 1H), 3.42 (s,br, 1H), 3.59 (m, 1H), 4.17 (s, br, 1H), 4.42 (s, br, 1H), 7.19 (m, 2H),7.24 (s, 1H), 7.38 (m, 3H), 7.47 (s, br, 2H).

Mass Spectrum (ESI) m/z=595.2 (M+1).

Examples 292-294 were prepared using similar procedures as described forExample 272 starting with(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one(Example 253, Step C).

Example Reagent Used Source or CAS# 292 propane-2-sulfonamide[81363-76-0] 293 cyclobutanesulfonamide Example 271G 294cyclopentanesulfonamide [73945-39-8]

Example 2922-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(1-methylethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)propane-2-sulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.32 (s, br, 1H), 0.01 (s, br, 1H),0.36 (d, br, 2H), 0.71 (t, J=8 Hz, 3H), 0.78 (m, 1H), 1.17 (m, 6H), 1.32(m, 1H), 1.58 (dd, J=4, 12 Hz, 1H), 1.70-1.79 (m, 1H), 2.03 (t, J=12 Hz,1H), 2.37 (dd, J=4, 12 Hz, 1H), 2.47 (dd, J=4, 12 Hz, 1H), 2.86 (s, br,1H), 2.93 (m, 1H), 3.02 (m, 2H), 4.59 (d, J=12 Hz, 1H), 4.98 (s, 1H),5.00 (d, J=8 Hz, 1H), 5.27 (s, 1H), 5.72 (m, 1H), 6.56 (d, J=8 Hz, 2H),6.77 (s, 1H), 6.89-6.97 (m, 3H), 6.98 (s, br, 2H).

Mass Spectrum (ESI) m/z=577.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(1-methylethylsulfonamido)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, chloroform-d₁) δ ppm −0.47 (s, br, 1H), 0.00 (s, br,1H), 0.41 (s, br, 1H), 0.48 (s, br, 1H), 0.97 (t, J=8 Hz, 3H), 1.32 (m,7H), 1.80 (m, 1H), 1.94 (m, 2H), 2.38 (t, J=12 Hz, 3H), 2.64 (d, J=16Hz, 1H), 2.70 (s, br, 1H), 2.91 (d, J=16 Hz, 1H), 3.01 (s, br, 1H), 3.19(m, 1H), 3.40 (m, 1H), 3.53 (s, br, 1H), 4.94 (s, br, 1H), 7.00 (m, 2H),7.06 (s, 1H), 7.17 (m, 3H), 7.25 (s, br, 2H). Mass Spectrum (ESI)m/z=595.2 (M+1).

Example 2932-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclobutanesulfonamide

Mass Spectrum (ESI) m/z=589.2 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.48 (s, br, 1H), −0.01 (s, br,1H), 0.40 (s, br, 1H), 0.48 (s, br, 1H), 0.97 (t, J=8 Hz, 3H), 1.33 (s,br, 1H), 1.81 (m, 1H), 1.94-2.05 (m, 4H), 2.34 (m, 2H), 2.37 (m, 3H),2.64 (d, J=12 Hz, 1H), 2.72 (s, br, 1H), 2.91 (d, J=12 Hz, 1H), 3.00 (s,br, 1H), 3.39 (m, 2H), 3.90 (m, 1H), 4.92 (s, br, 1H), 6.99 (m, 2H),7.05 (s, br, 1H), 7.15 (m, 3H), 7.25 (s, br, 2H). Mass Spectrum (ESI)m/z=607.0 (M+1).

Example 2942-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-1-yl)-2-cyclopropylethyl)cyclopentanesulfonamide

¹H NMR (400 MHz, methanol-d₄) δ ppm −0.32 (s, br, 1H), 0.00 (s, br, 1H),0.36 (s, br, 1H), 0.38 (s, br, 1H), 0.71 (t, J=8 Hz, 3H), 0.78 (m, 1H),1.33 (m, 1H), 1.44 (m, 2H), 1.58 (m, 3H), 1.80 (m, 6H), 2.03 (t, J=12Hz, 1H), 2.36 (dd, J=8 Hz, 16, 1H), 2.46 (dd, J=8, 16 Hz, 1H), 2.85 (s,br, 2H), 3.01 (m, 2H), 3.24 (m, 1H), 4.59 (d, J=12 Hz, 1H), 4.97 (s,1H), 5.00 (d, J=4Hz, 1H), 5.32 (s, br, 1H), 5.72 (m, 1H), 6.56 (s, 1H),6.58 (s, 1H), 6.77 (s, 1H), 6.91 (m, 3H), 6.98 (s, br, 2H). MassSpectrum (ESI) m/z=603.3 (M+1).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentanesulfonamido)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, chloroform-d₁) δ ppm −0.47 (s, br, 1H), 0.01 (s, br,1H), 0.41 (s, br, 1H), 0.48 (s, br, 1H), 0.96 (t, J=12 Hz, 3H), 1.42 (s,br, 1H), 1.65 (m, 2H), 1.71 (m, 3H), 1.96 (m, 6H), 2.37 (t, J=12 Hz,1H), 2.64 (d, J=16 Hz, 1H), 2.71 (s, br, 1H), 2.91 (d, J=16 Hz, 1H),2.97 (s, br, 1H), 3.40 (m, 1H), 3.54 (m, 2H), 4.93 (s, br, 1H), 7.00 (s,1H), 7.01 (s, 1H), 7.05 (s, 1H), 7.14 (m, 3H), 7.25 (s, br, 2H). MassSpectrum (ESI) m/z=621.1 (M+1).

Example 2952-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutyl)-N-methylcyclopropanesulfonamide

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one(Example 261, Step H, 109 mg, 0.237 mmol) andN-methylcyclopropanesulfonamide (WO2005/108358, 120 mg, 0.888 mmol)using the general procedure described in Step A of Example 272 and waspurified by silica chromatography eluting with ethyl acetate in hexanes.The product was obtained as a beige foam (113.5 mg, 83%). LCMS (ESI):m/z=577.2 (M+H).

Step B:2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

A mixture ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutyl)-N-methylcyclopropanesulfonamide(Example 295, Step A, 112.5 mg, 0.195 mmol), sodium periodate (170 mg,0.795 mmol), and ruthenium(III) chloride hydrate (6 mg, 0.023 mmol) inacetonitrile (1.0 mL), carbon tetrachloride (1.0 mL), and water (1.5 mL)was vigorously stirred at ambient temperature overnight. The reactionmixture was acidified with aqueous citric acid (10% by weight), dilutedin ethyl acetate, and filtered through a pad of Celite® (J.T. Baker,Phillipsberg, N.J., diatomaceous earth). The filtrate was partitionedbetween 2 M aqueous HCl and ethyl acetate. Combined organics were washedwith brine, dried over sodium sulfate, filtered, and concentrated invacuo to a residue that was purified by preparative HPLC (Sunfire™ PrepC₁₈ OBD 10 μm column, 30×150 mm, Waters, Milford, Mass.) eluting with agradient of 50 to 100% acetonitrile in water (0.1% trifluoroacetic acidin both solvents). Chromatography fractions containing the product werestripped of volatiles, redissolved in minimal volumes of acetonitrileand water, frozen, and lyophilized to give the product as a white solid.

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.63 (d, J=6.60 Hz, 3 H), 0.69 (s, 3H), 0.95-1.22 (m, 4 H), 1.40 (s, 3 H), 2.07 (dd, J=13.7, 3.2 Hz, 1 H),2.23 (dquin, J=9.5, 6.7 Hz, 1 H), 2.38 (t, J=13.7 Hz, 1 H), 2.51-2.60(m, 1H), 2.60-2.71 (m, 2 H), 2.87-2.96 (m, 4 H), 3.01 (d, J=13.5 Hz, 1H), 3.48 (ddd, J=13.8, 11.0, 3.1 Hz, 1 H), 4.13-4.40 (m, 1 H), 4.97 (d,J=11.0 Hz, 1 H), 6.98-7.06 (m, 2 H), 7.07-7.16 (m, 2 H), 7.29 (br s, 4H). LCMS (ESI): m/z=595.2 (M+H).

Example 2962-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropanesulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutyl)cyclopropanesulfonamide

The title compound was prepared using cyclopropanesulfonamide (101 mg,0.834 mmol) according to the procedure described in Step A of Example272 and purified by silica chromatography eluting with a gradient ofethyl acetate in hexanes. The product was obtained as a solid. LCMS(ESI): m/z=563.2 (M+H).

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropanesulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxoppiperidin-3-yl)aceticacid

The title compound was prepared by the general procedure described instep B of Example 295. The product was obtained as an off-white powder.

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.59 (d, J=6.9 Hz, 3 H), 0.63 (d,J=6.4 Hz, 3 H), 0.95-1.10 (m, 3 H), 1.10-1.18 (m, 1 H), 1.42 (s, 3 H),2.09 (dd, J=13.7, 3.2 Hz, 1 H), 2.14-2.24 (m, 1 H), 2.38 (t, J=13.7 Hz,1 H), 2.52-2.61 (m, 1 H), 2.62-2.80 (m, 2 H), 3.01 (d, J=13.5 Hz, 1 H),3.21 (dd, J=14.1, 2.1 Hz, 1 H), 3.51 (ddd, J=13.6, 11.2, 3.1 Hz, 1 H),3.83 (br s, 1 H), 5.07 (d, J=11.25 Hz, 1 H), 7.04 (d, J=7.34 Hz, 1 H),7.07-7.63 (m, 7 H). LCMS (ESI): m/z=581.2 (M+H).

Example 2972-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)-3-methylbutyl)ethanesulfonamide

The title compound was prepared from ethanesulfonamide (76 mg, 0.696mmol; Allichem) by the general procedure described in Step A of Example295, and purified by silica gel chromatography eluting with a gradientof ethyl acetate in hexanes. The product was obtained in 89% yield. LCMS(ESI) m/z=551.2 (M+H).

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared using the procedure described in Step Bof example 295 an obtained as a white solid (56% yield).

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.59 (d, J=6.9 Hz, 3 H), 0.62 (d,J=6.6 Hz, 3 H), 1.36 (t, J=7.5 Hz, 3 H), 1.42 (s, 3 H), 2.09 (d, J=10.5Hz, 1 H), 2.14-2.23 (m, 1 H), 2.34-2.47 (m, 1 H), 2.64 (s, 0 H), 2.70(br. s., 1 H), 3.02 (d, J=13.2 Hz, 1 H), 3.06-3.20 (m, 3 H), 3.53 (ddd,J=13.8, 11.1, 3.1 Hz, 1 H), 3.79 (br. s., 1 H), 5.10 (d, J=11.0 Hz, 1H), 7.03-7.08 (m, 1 H), 7.09-7.17 (m, 3 H), 7.17-7.87 (m, 4 H). LCMS(ESI): m/z=569.2 (M+H).

Example 2982-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 91, Step B, 250 mg, 0.560 mmol) and cyclobutanesulfonamide(Example 271G, 256 mg, 1.894 mmol) using the general procedure describedin Step A of Example 272, albeit with an oil bath heated at 40° C. Thecrude product was purified by silica gel chromatography eluting with agradient of EtOAc in hexanes. The product was obtained as a white powder(220 mg, 70%). LCMS (ESI): m/z=563.2 (M+H).

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide(Example 298, Step A, 50 mg, 0.089 mmol) by the general proceduredescribed in Step B of Example 295. The crude product was purified bypreparative HPLC chromatography (Sunfire™ Prep C₁₈ OBD 10 μm column,30×150 mm, Waters, Milford, Mass.) eluting with a 50 to 95% gradient ofacetonitrile in water (0.1% trifluoroacetic acid in both solvents) toafford a white powder.

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.44 (t, J=7.6 Hz, 3 H), 1.42 (s, 3H), 1.50-1.63 (m, 1 H), 1.73-1.88 (m, 1 H), 1.94-2.14 (m, 3 H),2.20-2.53 (m, 5 H), 2.62 (s, 1 H), 2.80 (t, J=9.2 Hz, 1 H), 2.87-3.01(m, 2 H), 3.32-3.39 (m, 1 H), 3.80 (dd, J=13.9, 10.0 Hz, 1 H), 3.92(quin, J=8.25 Hz, 1 H), 4.93 (d, J=11.00 Hz, 1 H), 7.03 (d, J=7.3 Hz, 1H), 7.08 (s, 1 H), 7.11-7.22 (m, 4 H), 7.26 (d, J=7.6 Hz, 2 H). LCMS(ESI): m/z=581.2 (M+H).

Example 2992-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylcyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-ethylcyclobutanesulfonamide

By the method of Example 290, Step A,N—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclobutanesulfonamide(Example 298, Step A) was treated with ethyl iodide to afford the titlecompound as a white foam. LCMS (ESI) m/z=591.2 (M+H).

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-ethylcyclobutanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared fromN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-ethylcyclobutanesulfonamide(Example 299, Step A) by the general procedure described in Step B ofExample 295 and obtained as a fluffy white solid.

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.50 (t, J=7.21 Hz, 3 H), 1.05-1.13(m, 3 H), 1.43 (s, 3 H), 1.54-1.67 (m, 1 H), 1.88 (dquin, J=15.2, 7.5Hz, 1 H), 1.93-2.12 (m, 3 H), 2.22-2.36 (m, 2 H), 2.37-2.59 (m, 3 H),2.64 (d, J=13.20 Hz, 1 H), 2.70-2.99 (m, 3 H), 3.17 (dq, J=14.6, 7.2 Hz,1 H), 3.33-3.43 (m, 1 H), 3.96 (quin, J=8.4 Hz, 1 H), 4.06-4.33 (m, 1H), 4.83 (m, 1H), 7.02 (d, J=7.1 Hz, 1 H), 7.05 (s, 1 H), 7.08-7.21 (m,3 H), 7.27 (br. s., 3 H). LCMS (ESI): m/z=609.2 (M+H).

Example 3002-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(phenylsulfonyl)butan-2-yl)piperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(phenylthio)butan-2-yl)piperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(180 mg, 0.403 mmol; Example 91, Step B) in 2 mL of toluene was addedcyanomethylenetributylphosphorane (324 uL, 1.21 mmol) and benzenethiol(121 μL, 1.21 mmol) at RT. The mixture was heated to 110° C. for 2 h.The reaction was cooled down, quenched (sat. aq. NH₄Cl solution),extracted (2×EtOAc), and washed with brine. The combined organic layerswere dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. Purification of the residue by chromatography onsilica gel (4 g SiO₂, 10, 20, 40% EtOAc/hexane) provided the titlecompound.

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(phenylsulfonyl)butan-2-yl)piperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(phenylthio)butan-2-yl)piperidin-2-one(Example 300, Step A) by a procedure similar to the one described inExample 71, Step F. The crude product was purified by reverse phasepreparatory HPLC (Gemini™ Prep C₁₈ 5 μm column; Phenomenex, Torrance,Calif.; MeCN in water with 0.1% TFA, gradient elution) to give a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.37 (t, J=8 Hz, 3 H), 1.46 (m, 1 H), 1.58(s, 3 H), 1.94 (dd, J=12, 4 Hz, 1 H), 2.08 (m, 1 H), 2.50 (t, J=16 Hz, 1H), 2.79 (d, J=16 Hz, 1 H), 2.88 (dd, J=16 Hz, 1 H), 3.05 (d, J=16 Hz, 1H), 3.15 (m, 1 H), 3.41 (m, 1 H), 4.24 (dd, J=16, 12 Hz, 1 H), 5.04 (d,J=8.0 Hz, 1 H), 6.88 (d, J=8.0 Hz, 1 H), 6.99 (s, 1 H), 7.14 (m, 4 H),7.27 (m, 2 H), 7.61 (m, 2 H), 7.71 (m, 1 H), 7.93 (d, J=8 Hz, 2 H); MassSpectrum (ESI) 588.1 [M+H]⁺.

Example 3012-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(((trimethylsilyl)methyl)thio)butan-2-yl)piperidin-2-one

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 91, Step B) by a procedure similar to the one described inExample 300, Step A, replacing benzenethiol with the appropriate amountof (trimethylsilyl)methanethiol.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylthio)butan-2-yl)piperidin-2-one

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(((trimethylsilyl)methyl)thio)butan-2-yl)piperidin-2-one(60 mg, 0.118 mmol, Example 301, Step A) was dissolved in a 1 M solutionof tetrabutylammonium fluoride in tetrahydrofuran (3.5 mL, 3.5 mmol) atroom temperature. The resulting solution was stirred at ambienttemperature for 16 h. After that time volatiles were removed underreduced pressure, and the residue was purified by chromatography onsilica gel (4 g SiO₂, 10, 20, 40% EtOAc/hexane) to provide the titlecompound.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylthio)butan-2-yl)piperidin-2-one(Example 301, Step B) to by a procedure similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.42 (t, J=8.0 Hz, 3 H), 1.45 (m, 1 H),1.48 (s, 3 H), 1.90 (d, J=12 Hz, 1 H), 2.14 (m, 1 H), 2.37 (t, J=16.0Hz, 1 H), 2.76 (d, J=16 Hz, 1 H), 2.90 (d, J=12 Hz, 1 H), 2.97 (m, 1 H),2.99 (s, 3 H), 3.13 (m, 1 H), 3.37 (m, 1 H), 4.24 (m, 1 H), 4.90 (d,J=8.0 Hz, 1 H), 6.84 (d, J=8.0 Hz, 1 H), 6.95 (s, 1 H), 7.12 (m, 4 H),7.27 (m, 2 H); Mass Spectrum (ESI) 526.0 [M+H]⁺.

Examples 302 to 311 were also prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 91, Step B) by procedures similar to the one described inExample 300, replacing benzenethiol with the appropriate amount ofthiol. The requisite thiols are either commercially available, preparedas described in the table below or are prepared by the following generalprocedure from the corresponding alcohols.

General Thiol Procedure

Methanesulfonyl chloride (1 eq.) was added dropwise to a 0.5 M solutionof the corresponding alcohol and triethylamine (1 eq.) indichloromethane. The resulting mixture was stirred rt for 2 h. Thereaction was then partitioned with water, washed with brine, dried oversodium sulfate, filtered and concentrated. This material was dissolvedin DMF to give a 0.5M solution of the mesylate. To this sodiumhydrosulfide (1.2 eq.) was added. The resulting mixture was stirredovernight at 45° C. The mixture was then partitioned with ether/water,washed with brine, dried over sodium sulfate, filtered the filtrate wasconcentrated under reduced pressure. The crude thiol obtained was usedin the next step without further purification.

Example R Reagent used 302

1-propanethiol 303

2-methyl-1-propanethiol 304

cyclopropylmethanethiol; prepared from bromomethylcyclopropane by theprocedure described in U.S. Pat. No. 3,975,429. 305

cyclobutylmethanethiol; prepared from bromomethylcyclobutane by aprocedure similar to the one described for the preparation ofcyclopropylmethanethiol in U.S. Pat. No. 3,975,429. 306

cyclopentanethiol; prepared from bromocyclopentane by a proceduresimilar to the one described for the preparation ofcyclopropylmethanethiol in U.S. Pat. No. 3,975,429. 307

oxetan-3-ylmethanethiol 308

prepared by general procedure above 309

prepared by general procedure above 310

prepared by general procedure above 311

butane-2-thiol 312

butane-2-thiol

Example 3022-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-(propylsulfonyl)butan-2-yl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23-7.27 (2 H, m), 7.01-7.21 (4 H,m), 6.93-7.00 (1 H, m), 6.84 (1 H, dt, J=7.1, 1.6 Hz), 4.93 (1 H, d,J=10.8 Hz), 4.05-4.20 (1 H, m), 3.33 (1 H, t, J=10.1 Hz), 3.12 (1 H,ddd, J=13.7, 10.9, 2.6 Hz), 2.95-3.04 (3 H, m), 2.71-2.85 (2 H, m), 2.38(1 H, t, J=13.8 Hz), 2.14 (1 H, ddd, J=14.3, 9.9, 7.3 Hz), 1.86-1.98 (3H, m), 1.49 (3 H, s), 1.39-1.48 (1 H, m), 1.13 (3 H, t, J=7.5 Hz), 0.41(3 H, t, J=7.5 Hz); Mass Spectrum (ESI) 554.2 [M+H]⁺.

Example 3032-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isobutylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.27-7.24 (2 H, m), 7.02-7.20 (4 H,m), 6.93-7.00 (1 H, m), 6.84 (1 H, dt, J=7.2, 1.5 Hz), 4.93 (1 H, d,J=10.6 Hz), 4.15 (1 H, t, J=12.2 Hz), 3.33 (1 H, t, J=9.5 Hz), 3.13 (1H, ddd, J=13.6, 10.9, 2.6 Hz), 2.84-3.03 (3 H, m), 2.66-2.83 (2 H, m),2.33-2.47 (2 H, m), 2.12 (1H, ddd, J=14.3, 9.9, 7.3 Hz), 1.90 (1 H, dd,J=13.7, 2.7 Hz), 1.48 (3 H, s), 1.40-1.47 (1 H, m), 1.17 (3 H, d, J=6.8Hz), 1.15 (3 H, d, J=6.8 Hz) 0.41 (3 H, t, J=7.5 Hz); Mass Spectrum(ESI) 568.2 [M+H]⁺.

Example 3042-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclopropylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23-7.27 (2 H, m), 7.00-7.22 (4 H,m), 6.94-6.98 (1 H, m), 6.85 (1 H, dt, J=7.1, 1.5 Hz), 4.95 (1 H, d,J=10.8 Hz), 4.17 (1 H, t, J=12.1 Hz), 3.35 (1 H, t, J=9.7 Hz), 3.13 (1H, ddd, J=13.6, 10.9, 2.7 Hz), 2.83-3.07 (4 H, m), 2.77 (1 H, d, J=14.9Hz), 2.39 (1 H, t, J=13.8 Hz), 2.07-2.22 (1 H, m), 1.91 (1 H, dd,J=13.9, 2.7 Hz), 1.48 (3 H, s), 1.40-1.47 (1 H, m), 1.12-1.25 (1 H, m),0.75-0.85 (2 H, m), 0.37-0.48 (5 H, m); Mass Spectrum (ESI) 566.2[M+H]⁺.

Example 3052-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((cyclobutylmethyl)sulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.27 (2 H, m), 6.99-7.20 (4 H,m), 6.93-6.98 (1 H, m), 6.84 (1 H, dt, J=7.2, 1.4 Hz), 4.91 (1 H, d,J=10.8 Hz), 4.09 (1 H, t, J=12.2 Hz), 3.31 (1 H, t, J=10.1 Hz),3.05-3.18 (3 H, m), 2.84-3.02 (2 H, m), 2.67-2.82 (2 H, m), 2.36 (1 H,t, J=13.8 Hz), 2.20-2.31 (2 H, m), 2.01-2.18 (2 H, m), 1.82-1.97 (4 H,m), 1.47 (3 H, s), 1.38-1.46 (1 H, m), 0.40 (3 H, t, J=7.5 Hz); MassSpectrum (ESI) 580.2 [M+H]⁺.

Example 3062-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopentylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.40 (t, J=8.0 Hz, 3 H), 1.46 (m, 1H), 1.49 (s, 3 H), 1.70 (m, 2 H), 1.80-1.95 (m, 3 H), 2.09 (m, 5 H),2.40 (t, J=12 Hz, 1 H), 2.76 (d, J=16.0 Hz, 2 H), 3.00 (d, J=16 Hz, 1H), 3.12 (m, 1 H), 3.36 (m, 2 H), 4.10 (t, J=12 Hz, 1 H), 4.97 (d, J=8.0Hz, 1 H), 6.85 (d, J=8.0 Hz, 1 H), 6.96 (s, 1 H), 7.12 (m, 4 H), 7.25(m, 2 H); Mass Spectrum (ESI) 580.1 [M+H]⁺.

Example 3072-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(oxetan-3-ylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CD₃OD) δ ppm 0.39 (t, J=7.63 Hz, 3 H) 1.34-1.43 (m, 3H) 1.46-1.63 (m, 1 H) 2.02-2.10 (m, 2 H) 2.29 (t, J=13.69 Hz, 1 H) 2.61(d, J=13.69 Hz, 1 H) 2.95 (d, J=13.69 Hz, 1 H) 2.98-3.07 (m, 1 H) 3.41(ddd, J=13.60, 10.96, 2.84 Hz, 1 H) 3.94-4.20 (m, 1 H) 4.55-4.76 (m, 1H) 4.87-4.93 (m, 4 H) 4.94-5.01 (m, 2 H) 6.97 (dt, J=6.65, 1.76 Hz, 1 H)7.00-7.07 (m, 1 H) 7.07-7.22 (m, 3 H) 7.28 (br s, 3 H); Mass Spectrum(ESI) m/z=568 (M+1).

Example 3082-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(((3-methyloxetan-3-yl)methyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

1H NMR (500 MHz, CD₃OD) δ ppm −1.06 (br s, 1 H)-0.21 (br s, 1 H) 0.23(br s, 1 H) 0.37 (br s, 1 H) 1.22-1.30 (m, 3 H) 1.38-1.45 (m, 3 H)1.70-1.77 (m, 3 H) 1.99-2.09 (m, 1 H) 2.31 (t, J=13.69 Hz, 1 H)2.65-2.73 (m, 1 H) 2.95-3.03 (m, 1 H) 3.39-3.49 (m, 1 H) 3.59-3.66 (m, 1H) 3.66-3.73 (m, 1 H) 4.07-4.16 (m, 2 H) 4.40-4.45 (m, 2 H) 4.80 (d,J=6.11 Hz, 2 H) 4.91 (d, J=10.76 Hz, 2 H) 6.94-7.00 (m, 1 H) 7.06 (s, 1H) 7.08-7.22 (m, 3 H) 7.32 (br s, 3 H); Mass Spectrum (ESI) m/z=608(M+1).

Example 3092-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-((tetrahydro-2H-pyran-4-yl)sulfonyl)butan-2-yl)piperidin-3-yl)aceticacid

¹H NMR (400 MHz, CD₃OD) δ ppm 0.41 (t, J=7.53 Hz, 3 H) 1.26 (t, J=7.14Hz, 2 H) 1.39 (s, 3 H) 1.87 (dd, J=12.52, 4.50 Hz, 2 H) 2.04-2.16 (m, 4H) 2.28 (t, J=13.69 Hz, 1 H) 2.61 (d, J=13.69 Hz, 1 H) 2.96 (d, J=13.69Hz, 1 H) 3.34-3.58 (m, 4 H) 3.98-4.26 (m, 4 H) 4.98 (d, J=10.96 Hz, 1 H)6.97 (dt, J=6.55, 1.81 Hz, 1 H) 7.04 (s, 1 H) 7.09-7.22 (m, 3 H) 7.30(br s, 3 H); Mass Spectrum (ESI) m/z=596 (M+1).

Example 3102-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((2-hydroxy-2-methylpropyl)sulfonyl)butan-2-O-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CD₃OD) δ ppm 0.38 (t, J=7.43 Hz, 3 H) 1.17-1.27 (m, 2H) 1.38 (s, 3 H) 1.44 (s, 6 H) 1.46-1.56 (m, 1 H) 2.01-2.12 (m, 2 H)2.26 (t, J=13.69 Hz, 1 H) 2.50-2.66 (m, 1 H) 2.94 (d, J=13.50 Hz, 1 H)3.33-3.46 (m, 3 H) 4.19 (dd, J=13.99, 11.05 Hz, 1 H) 4.97 (d, J=10.76Hz, 1 H) 6.85-6.99 (m, 1 H) 7.03 (s, 1 H) 7.08-7.18 (m, 3 H) 7.26 (br s,3 H); Mass Spectrum (ESI) m/z=584 (M+1).

Example 3112-((3R,5R,6S)-1-((S)-1-((R)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-1-((S)-1-((S)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The crude product was purified by reversed phase preparatory HPLC(Gemini™ Prep C₁₈ 5 mm column; Phenomenex, Torrance, Calif.) (gradientelution of 50% to 85% MeCN in water, where both solvents contain 0.1%TFA, 27 min method) to provide the title compound as the faster elutingisomer (t_(R)=9.43 min).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24 (d, J=7.43 Hz, 2H), 7.04-7.15(m, 3H), 6.96 (s, 1H), 6.85 (td, J=1.83, 6.70 Hz, 1H), 4.96 (d, J=10.56Hz, 1H), 4.15 (ddd, J=3.13, 10.81, 13.45 Hz, 1H), 3.29 (t, J=10.17 Hz,1H), 3.14 (ddd, J=2.93, 10.86, 13.60 Hz, 1H), 2.77-2.93 (m, 2H),2.62-2.74 (m, 2H), 2.38 (t, J=13.79 Hz, 1H), 2.02-2.20 (m, 2H), 1.85(dd, J=2.84, 13.79 Hz, 1H), 1.54-1.66 (m, 1H), 1.37-1.53 (m, 7H), 1.08(dt, J=3.33, 7.43 Hz, 3H), 0.41 (t, J=7.53 Hz, 3H). Mass Spectrum (ESI)m/z=668.2 [M]⁺.

Example 3122-((3R,5R,6S)-1-((S)-1-((R)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-1-((S)-1-((S)-sec-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The crude product was purified by reversed phase preparatory HPLC(Gemini™ Prep C18 5 mm column; Phenomenex, Torrance, Calif.) (gradientelution of 50% to 85% MeCN in water, where both solvents contain 0.1%TFA) to provide the title compound as the slower eluting isomer(t_(R)=10.2 min).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.97 (t, J=2.74 Hz, 1H), 7.24 (d,J=7.43 Hz, 2H), 7.04-7.15 (m, 3H), 6.96 (s, 1H), 6.85 (td, J=1.83, 6.70Hz, 1H), 4.96 (d, J=10.56 Hz, 1H), 4.15 (ddd, J=3.13, 10.81, 13.45 Hz,1H), 3.29 (t, J=10.17 Hz, 1H), 3.14 (ddd, J=2.93, 10.86, 13.60 Hz, 1H),2.77-2.93 (m, 2H), 2.62-2.74 (m, 2H), 2.38 (t, J=13.79 Hz, 1H),2.02-2.20 (m, 2H), 1.85 (dd, J=2.84, 13.79 Hz, 1H), 1.54-1.66 (m, 1H),1.37-1.53 (m, 7H), 1.08 (dt, J=3.33, 7.43 Hz, 3H), 0.41 (t, J=7.53 Hz,3H); Mass Spectrum (ESI) m/z=668.2 [M]⁺.

Examples 313 to 323 were prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 252, Step A) by procedures similar to the one described inExample 300, replacing benzenethiol with the appropriate amount ofthiol.

Example R Reagent used 313

cyclopentanethiol; prepared from bromocyclopentane by a proceduresimilar to the one described for the preparation ofcyclopropylmethanethiol in U.S. Pat. No. 3,975,429. 314

example 308 315

benzenethiol 316

o-toluenethiol 317

2-chlorobenzenethiol 318

4-chlorobenzenethiol 319

4-fluorobenzenethiol 320

4-mercaptopyridine 321

2-chloro-4-fluorobenzenethiol (Oakwood Products, West Columbia, SC) 322

cyclopropylmethanethiol; prepared from bromomethylcyclopropane by aprocedure similar to the one described in U.S. Pat. No. 3,975,429. 323

2,2,2-trifluoroethanethiol

Example 3132-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentylsulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.08 (br. s, 1 H)-0.30 (br. s, 1H) 0.21-0.29 (m, 1 H) 0.33-0.42 (m, 1 H) 1.51 (s, 3 H) 1.65-1.77 (m, 2H) 1.80-1.92 (m, 4 H) 2.10 (m, 4 H) 2.48 (t, J=13.79 Hz, 1 H) 2.75 (m, 2H) 2.89 (dd, J=13.60, 2.25 Hz, 1 H) 3.09-3.18 (m, 2 H) 3.38 (quin,J=8.02 Hz, 1 H) 4.33 (m 1 H) 4.92 (d, J=10.56 Hz, 1 H) 6.84-6.90 (m, 1H) 6.95 (s, 1 H) 7.07-7.17 (m, 2 H) 7.37 (m., 4 H); Mass Spectrum (ESI)m/z=592 (M+1).

Example 3142-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((3-methyloxetan-3-yl)methyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CD₃OD) δ ppm −1.06 (br s, 1 H)-0.21 (br s, 1 H) 0.23(br s, 1 H) 0.37 (br s, 1 H) 1.22-1.30 (m, 3 H) 1.38-1.45 (m, 3 H)1.70-1.77 (m, 3 H) 1.99-2.09 (m, 1 H) 2.31 (t, J=13.69 Hz, 1 H)2.65-2.73 (m, 1 H) 2.95-3.03 (m, 1 H) 3.39-3.49 (m, 1 H) 3.59-3.66 (m, 1H) 3.66-3.73 (m, 1 H) 4.07-4.16 (m, 2 H) 4.40-4.45 (m, 2 H) 4.80 (d,J=6.11 Hz, 2 H) 4.91 (d, J=10.76 Hz, 2 H) 6.94-7.00 (m, 1 H) 7.06 (s, 1H) 7.08-7.22 (m, 3 H) 7.32 (br s, 3 H); Mass Spectrum (ESI) m/z=608(M+1).

Example 3152-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(phenylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −1.12-−1.02 (m, 1 H)-0.33 (m, 1 H)0.19-0.27 (m, 1 H) 0.29-0.35 (m, 1 H) 1.60 (s, 3 H) 1.77-1.89 (m, 1 H)1.92 (dd, J=13.69, 2.93 Hz, 1 H) 2.57 (t, J=13.94 Hz, 1 H) 2.81 (d,J=15.16 Hz, 2 H) 3.00 (dd, J=13.94, 2.45 Hz, 1 H) 3.08-3.25 (m, 2 H)4.47 (t, J=12.35 Hz, 1 H) 5.01 (d, J=10.51 Hz, 1 H) 6.90 (dt, J=7.03,1.62 Hz, 1 H) 6.96-7.02 (m, 1 H) 7.07-7.19 (m, 2 H) 7.20-7.30 (m, 4 H)7.56-7.67 (m, 2 H) 7.67-7.77 (m, 1 H) 7.87-7.98 (m, 2 H); Mass Spectrum(ESI) m/z=600 (M+1).

Example 3162-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(o-tolylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.00 (1 H, dd, J=7.9, 1.1 Hz),7.51-7.64 (1 H, m), 7.34-7.48 (3 H, m), 7.22-7.34 (2 H, m), 7.06-7.18 (3H, m), 6.98-7.04 (1 H, m), 6.86-6.96 (1 H, m), 5.02 (1 H, d, J=10.8 Hz),4.60 (1 H, t, J=12.4 Hz), 3.20 (1 H, ddd, J=13.7, 10.8, 2.7 Hz), 3.09 (1H, d, J=14.9 Hz), 2.99 (1 H, dd, J=14.0, 2.2 Hz), 2.77-2.87 (2 H, m),2.71 (3 H, s), 2.53 (1 H, t, J=13.8 Hz), 1.94 (1 H, dd, J=13.8, 2.8 Hz),1.78-1.86 (1 H, m), 1.56 (3 H, s), 0.17-0.40 (2 H, m), −0.40-−0.30 (1 H,m), −1.12-−1.00 (1 H, m); Mass Spectrum (ESI) 614.2 [M+H]⁺.

Example 3172-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −1.08 (br s, 1 H)-0.27 (m, 1 H)0.20-0.29 (m, 1 H) 0.31-0.40 (m, 1 H) 1.58 (s, 3 H) 1.82-1.96 (m, 2 H)2.53 (t, J=13.82 Hz, 1 H) 2.77-2.90 (m, 2 H) 3.11-3.22 (m, 2 H) 3.37(dd, J=13.94, 2.45 Hz, 1 H) 4.76 (t, J=12.23 Hz, 1 H) 4.97 (d, J=10.51Hz, 1 H) 6.89 (d, J=7.09 Hz, 1 H) 7.00 (s, 1 H) 7.09-7.19 (m, 2 H)7.27-7.35 (m, 4 H) 7.49-7.57 (m, 1 H) 7.57-7.68 (m, 2 H) 8.15 (dd,J=7.83, 1.47 Hz, 1 H); Mass Spectrum (ESI) m/z=636 (M+1).

Example 3182-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((4-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.38-−0.22 (m, 1 H) 0.26 (br s, 1H) 0.33 (dd, J=8.93, 4.52 Hz, 2 H) 1.59 (s, 3 H) 1.83 (br s, 1 H) 1.96(dd, J=13.82, 2.81 Hz, 1 H) 2.55 (t, J=13.94 Hz, 1 H) 2.84 (d, J=15.16Hz, 2 H) 2.98 (dd, J=13.94, 2.45 Hz, 1 H) 3.11 (d, J=14.92 Hz, 1 H) 3.22(ddd, J=13.69, 10.76, 2.93 Hz, 1 H) 4.99 (d, J=10.51 Hz, 1 H) 6.88-6.96(m, 1 H) 6.98-7.03 (m, 1 H) 7.09-7.21 (m, 2 H) 7.29 (m, 4 H) 7.56-7.66(m, 2 H) 7.83-7.94 (m, 2 H); Mass Spectrum (ESI) m/z=636 (M+1).

Example 3192-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((4-fluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −1.05 (br s, 1 H)-0.33 (br s, 1 H)0.17-0.38 (m, 2 H) 1.59 (s, 3 H) 1.76-1.88 (m, 1 H) 1.93 (dd, J=13.82,2.81 Hz, 1 H) 2.55 (t, J=13.82 Hz, 1 H) 2.82 (m, 2 H) 2.98 (dd, J=13.94,2.45 Hz, 1 H) 3.06-3.28 (m, 2 H) 4.48 (t, J=12.10 Hz, 1 H) 4.99 (d,J=10.51 Hz, 1 H) 6.89 (dt, J=7.09, 1.59 Hz, 1 H) 6.95-7.04 (m, 1 H)7.06-7.21 (m, 2 H) 7.21-7.40 (m, 6 H) 7.86-8.01 (m, 2 H); Mass Spectrum(ESI) m/z=618 (M+1).

Example 3202-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyridin-4-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −1.01 (br s, 1 H)-0.30 (br s, 1 H)0.28 (br s, 1 H) 0.30-0.46 (m, 1 H) 1.58 (s, 3 H) 1.83 (br s, 1 H) 1.96(dd, J=13.94, 2.93 Hz, 1 H) 2.52 (t, J=13.94 Hz, 1 H) 2.83 (m, 2 H) 3.00(dd, J=13.94, 2.45 Hz, 1 H) 3.11 (d, J=15.16 Hz, 1 H) 3.21 (ddd,J=13.69, 10.64, 2.81 Hz, 1 H) 4.55 (br s, 1 H) 4.94 (d, J=10.51 Hz, 1 H)6.88 (d, J=7.09 Hz, 1 H) 6.99 (s, 1 H) 7.08-7.20 (m, 2 H) 7.20-7.39 (m,4 H) 7.77-7.83 (m, 2 H) 8.92-8.99 (m, 2 H); Mass Spectrum (ESI) m/z=601(M+1).

Example 3212-((3R,5R,6S)-1-((S)-2-((2-Chloro-4-fluorophenyl)sulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.05 (br s, 1H), −0.29 (br s, 1H),0.25 (br s, 1H), 0.29-0.44 (m, 1H), 1.56 (s, 3H), 1.84 (br s, 1H),1.89-2.03 (m, 1H), 2.50 (t, J=13.89 Hz, 1H), 2.82 (d, J=14.87 Hz, 2H),3.08 (d, J=14.67 Hz, 1H), 3.15-3.26 (m, 1H), 3.31 (d, J=13.69 Hz, 1H),4.75 (br s, 1H), 4.96 (d, J=10.56 Hz, 1H), 6.89 (d, J=6.85 Hz, 1H), 7.00(s, 1H), 7.08-7.18 (m, 3H), 7.18-7.25 (m, 2H), 7.26-7.31 (m, 1H), 7.33(dd, J=7.92, 2.25 Hz, 2H), 8.17 (dd, J=8.80, 5.87 Hz, 1H); Mass Spectrum(ESI) m/z=652.0 and 653.9 (M+1).

Example 3222-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((cyclopropylmethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.06 (m, 1 H), −0.27 (m, 1 H),0.39 (m, 1 H), 0.43 (m, 3 H), 0.80 (m, 2 H), 1.18 (m, 1 H), 1.52 (s, 3H), 1.85 (d, J=12 Hz, 1 H), 1.95 (m, 1 H), 2.44 (t, J=12 Hz, 1 H), 2.76(d, J=16 Hz, 2 H), 2.90 (m, 1 H), 3.02 (m, 2 H), 3.14 (m, 2 H), 4.39 (m,1 H), 4.92 (d, J=12 Hz, 1 H), 6.86 (d, J=8.0 Hz, 1 H), 6.96 (s, 1 H),7.13 (m, 3 H), 7.27 (m, 3 H); Mass Spectrum (ESI) m/z=578.0 [M+H]⁺.

Example 3232-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(2,2,2-trifluoroethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.08-7.17 (2 H, m), 6.95 (1 H, s),6.83 (1 H, d, J=7.3 Hz), 4.79 (1 H, d, J=10.5 Hz), 3.80-3.93 (2 H, m),3.11-3.23 (2 H, m), 3.04 (1 H, d, J=14.7 Hz), 2.82 (2 H, d, J=14.7 Hz),2.37 (1 H, t, J=13.7 Hz), 1.94 (1 H, d, J=13.0 Hz), 1.49 (3 H, s), 0.43(1 H, br. s.), 0.31 (1 H, br. s.), −0.24 (1 H, br. s.), −1.03 (1 H, br.s.); Mass Spectrum (ESI) m/z=606 (M+1).

Example 3242-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((trifluoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((trifluoromethyl)thio)ethyl)-3-methylpiperidin-2-one

A mixture of ((trifluoromethyl)thio)copper (41.3 mg, 0.251 mmol, TCIAmerica, Portland, Oreg.), 2-(tributylphosphoranylidene)acetonitrile(194 mg, 0.803 mmol), and(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(115 mg, 0.251 mmol, Example 252, Step A) was stirred at 110° C. for 3h. A few drops of 4N HCl in dioxane were added and the mixture stirredfor 30 min Toluene (0.15 ml) was added and stirring continued at 110° C.for 20 h. HPLC purification (Gemini™ Prep C₁₈ 5 μm column; Phenomenex,Torrance, Calif.; gradient elution of 10% to 95% MeCN in water with 0.1%TFA) gave the title compound. Mass Spectrum (ESI) m/z=542 (M+1).

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((trifluoromethyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((trifluoromethyl)thio)ethyl)-3-methylpiperidin-2-one(Example 324, step A) by a procedure similar to the one described inExample 71,

Step F. The crude product was purified by reverse phase preparatory HPLC(Gemini™ Prep C₁₈ 5 μm column; Phenomenex, Torrance, Calif.; gradientelution of 10% to 95% MeCN in water, where both solvents contain 0.1%TFA).

¹H NMR (500 MHz, CDCl₃) δ ppm 7.10-7.17 (3 H, m), 6.93 (1 H, s),6.82-6.86 (1 H, m), 4.70 (1 H, d, J=10.5 Hz), 3.17-3.26 (2 H, m), 3.02(1 H, d, J=14.7 Hz), 2.85 (1 H, d, J=14.9 Hz), 2.77 (1 H, br. s.), 2.35(1 H, t, J=13.9 Hz), 1.99 (2 H, dd, J=13.9, 2.9 Hz), 1.51 (3 H, s), 1.26(1 H, s), 0.41-0.50 (1 H, m), 0.31 (1 H, br. s.), −0.23 (1 H, br. s.),−1.01 (1 H, br. s.); Mass Spectrum (ESI) m/z=592 (M+1).

Examples 325 to 335 were prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one(Example 253, Step C) by procedures similar to the one described inExample 300, replacing benzenethiol with the appropriate amount ofthiol.

Example R Reagent used 325

benzenethiol 326

2-chlorobenzenethiol 327

2-fluorobenzenethiol 328

3-fluorobenzenethiol 329

4-fluorobenzenethiol 330

propanethiol 331

butanethiol 332

3-methylbutanethiol 333

cyclopentanethiol; prepared from bromocyclopentane by a proceduresimilar to the one described for the preparation ofcyclopropylmethanethiol in U.S. Pat. No. 3,975,429. 334

cyclohexanethiol; prepared from bromocyclopentane by a procedure similarto the one described for the preparation of cyclopropylmethanethiol inU.S. Pat. No. 3,975,429. 335 Me— trimethylsilylmethanethiol (as perExample 301)

Example 3252-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(phenylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −1.01 (br. m., 1 H)-0.32 (br. m., 1H) 0.19-0.37 (m, 2 H) 1.06 (t, J=7.46 Hz, 3 H) 1.87 (m, 2 H) 2.02-2.17(m, 2 H) 2.54 (t, J=13.82 Hz, 1 H) 2.83 (m, 2 H) 3.03 (d, J=12.96 Hz, 1H) 3.07-3.23 (m, 2 H) 4.38 (br s, 1 H) 5.03 (d, J=10.51 Hz, 1 H) 6.91(d, J=7.09 Hz, 1 H) 6.98-7.04 (m, 1 H) 7.08-7.20 (m, 3 H) 7.48 (m, 3H)7.56-7.67 (m, 2 H) 7.67-7.78 (m, 1 H) 7.84-7.99 (m, 2 H);

Mass Spectrum (ESI) m/z=614 (M+1).

Example 3262-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-((2-chlorophenyl)sulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −1.01 (br. m., 1 H)-0.26 (br. m., 1H) 0.28 (br. m., 1 H) 0.31-0.44 (m, 1 H) 1.02 (t, J=7.46 Hz, 3 H) 1.88(m, 2 H) 2.02-2.16 (m, 2 H) 2.48 (t, J=13.82 Hz, 1 H) 2.83 (d, J=15.65Hz, 1 H) 2.90 (br s, 1 H) 3.07-3.23 (m, 2 H) 3.42 (dd, J=14.06, 2.08 Hz,1 H) 4.64 (br s, 1 H) 4.98 (d, J=10.51 Hz, 1 H) 6.89 (d, J=7.09 Hz, 1 H)6.97-7.04 (m, 1 H) 7.09-7.22 (m, 3 H) 7.33-7.48 (m, 3 H) 7.48-7.56 (m, 1H) 7.56-7.67 (m, 2 H) 8.14 (dd, J=7.95, 1.59 Hz, 1 H); Mass Spectrum(ESI) m/z=648 (M+1).

Example 3272-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((2-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.00 (br s, 1H), −0.26 (br s, 1H),0.19-0.45 (m, 2H), 1.02 (t, J=7.43 Hz, 3H), 1.87 (dd, J=13.69, 2.93 Hz,2H), 1.97-2.20 (m, 2H), 2.49 (t, J=13.79 Hz, 1H), 2.83 (d, J=15.26 Hz,2H), 3.08 (d, J=15.26 Hz, 1H), 3.19 (ddd, J=13.55, 10.71, 2.74 Hz, 1H),3.30 (d, J=13.89 Hz, 1H), 4.57 (br s, 1H), 4.95 (d, J=10.76 Hz, 1H),6.89 (d, J=6.85 Hz, 1H), 7.02 (s, 1H), 7.08-7.23 (m, 3H), 7.23-7.35 (m,3H), 7.35-7.52 (m, 2H), 7.67-7.81 (m, 1H), 7.91-8.05 (m, 1H); MassSpectrum (ESI) m/z=632.0 (M+1).

Example 3282-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((3-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.97 (br s, 1H), −0.31 (br s, 1H),0.18-0.48 (m, 2H), 1.05 (t, J=7.43 Hz, 3H), 1.88 (dd, J=13.79, 2.84 Hz,2H), 1.96-2.21 (m, 2H), 2.51 (t, J=13.79 Hz, 1H), 2.84 (d, J=15.06 Hz,2H), 2.95-3.13 (m, 2H), 3.13-3.31 (m, 1H), 4.41 (br s, 1H), 5.00 (d,J=10.56 Hz, 1H), 5.72 (br s, 2H), 6.91 (d, J=6.85 Hz, 1H), 7.01-7.04 (m,2H), 7.09-7.18 (m, 3H), 7.36-7.45 (m, 2H), 7.57-7.66 (m, 3H), 7.70 (d,J=7.83 Hz, 1H); Mass Spectrum (ESI) m/z=632.0 (M+1).

Example 3292-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((4-fluorophenyl)sulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.97 (br s, 1H), −0.31 (br s, 1H),0.32 (d, J=4.89 Hz, 2H), 1.05 (t, J=7.53 Hz, 3H), 1.26 (s, 1H), 1.88(dd, J=13.69, 2.93 Hz, 2H), 1.97-2.21 (m, 2H), 2.52 (t, J=13.79 Hz, 1H),2.83 (d, J=15.26 Hz, 1H), 2.92-3.13 (m, 2H), 3.13-3.30 (m, 1H), 4.38 (brs, 2H), 5.01 (d, J=10.56 Hz, 1H), 6.91 (d, J=6.65 Hz, 2H), 7.01 (s, 2H),7.07-7.22 (m, 3H), 7.28-7.37 (m, 3H), 7.83-8.03 (m, 2H); Mass Spectrum(ESI) m/e=632.0 (M+1).

Example 3302-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(propylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −0.71 (s, br, 1H), 0.00 (br s, 1H),0.51 (br s, 1H), 0.60 (br s, 1H), 1.19 (t, J=8 Hz, 3H), 1.32 (t, J=8 Hz,3H), 1.93-2.14 (m, 5H), 2.24 (m, 1H), 2.61 (t, J=12 Hz, 1H), 2.87 (d,J=12 Hz, 1H), 2.97 (br s, 1H), 3.13 (d, J=12 Hz, 1H), 3.32 (m, 3H), 3.69(m, 1H), 4.45 (s, br, 1H), 5.16 (d, J=12 Hz, 1H), 7.20-7.21 (d, J=4Hz,2H), 7.28 (s, 1H), 7.36 (m, 3H), 7.51 (br s, 2H); Mass Spectrum (ESI)m/z=580.2 (M+1).

Example 3312-((3R,5R,6S)-1-((S)-2-(Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −0.73 (s, br, 1H), 0.00 (br s, 1H),0.51 (br s, 1H), 0.60 (br s, 1H), 1.17-1.23 (m, 6H), 1.70-1.76 (m, 2H),2.01 (m, 4H), 2.13 (d, J=8 Hz, 1H), 2.24 (m, 1H), 2.61 (t, J=12 Hz, 1H),2.87 (d, J=16 Hz, 1H), 2.98 (br s, 1H), 4.14 (d, J=16 Hz, 1H), 3.31-3.42(m, 3H), 3.69 (m, 1H), 4.48 (br s, 1H), 5.17 (d, J=16 Hz, 1H), 7.20 (m,2H), 7.28 (s, 1H), 7.36 (m, 3H), 7.50 (br s, 2H); Mass Spectrum (ESI)m/z=594.2 (M+1).

Example 3322-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(isopentylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −0.73 (br s, 1H), 0.00 (br s, 1H),0.50 (br s, 1H), 0.60 (br s, 1H), 1.17-1.20 (m, 9H), 1.92 (m, 5H), 2.10(dd, J=4, 12 Hz, 1H), 2.24 (m, 1H), 2.61 (t, J=12 Hz, 1H), 2.87 (d, J=12Hz, 1H), 2.97 (br s, 1H), 3.13 (d, J=12 Hz, 1H), 3.37 (m, 3H), 3.69 (m,1H), 4.46 (br s, 1H), 5.16 (d, J=12 Hz, 1H), 7.20 (m, 2H), 7.27 (s, 1H),7.36 (m, 3H), 7.50 (br s, 2H); Mass Spectrum (ESI) m/z=608.2 (M+1).

Example 3332-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclopentylsulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −0.94 (br s, 1H), −0.23 (br s, 1H),0.30 (br s, 1H), 0.39 (br s, 1H), 0.99 (t, J=4Hz, 3H), 1.73-1.83 (m,6H), 1.87 (m, 1H), 2.05 (m, 5H), 2.42 (t, J=12 Hz, 1H), 2.68 (d, J=12Hz, 1H), 2.78 (br s, 1H), 2.94 (d, J=12 Hz, 1H), 3.48 (br s, 1H), 3.50(m, 1H), 3.61 (m, 1H), 4.27 (br s, 1H), 4.98 (d, J=12 Hz, 1H), 7.02 (d,J=8 Hz, 2H), 7.08 (s, 1H), 7.17 (m, 3H), 7.31 (br s, 2H); Mass Spectrum(ESI) m/z=606.2 (M+1).

Example 3342-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclohexylsulfonyl)-1-cyclopropylethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −0.97 (s, br, 1H), −0.25 (br s, 1H),0.29 (s, 1H), 0.39 (s, 1H), 0.99 (t, J=8 Hz, 3H), 1.24-1.52 (m, 6H),1.75-1.78 (m, 2H), 1.91-1.96 (m, 3H), 2.05 (m, 1H), 2.18 (s, br, 2H),2.39-2.46 (t, J=12 Hz, 1H), 2.68-2.71 (d, J=12 Hz, 1H), 2.78 (br s, 1H),2.94-2.98 (d, J=12 Hz, 1H), 3.08 (m, 2H), 3.48-3.53 (m, 1H), 4.27 (s,br, 1H), 4.99 (d, J=12 Hz, 1H), 7.01 (d, J=8 Hz, 2H), 7.08 (s, 1H),7.16-7.21 (m, 3H), 7.31 (s, br, 2H); Mass Spectrum (ESI) m/z=620.2 (M+1)

Example 3352-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, methanol-d4) δ ppm −0.71 (s, br, 1H), 0.00 m (s, br,1H), 0.47 (s, br, 1H), 0.55 (s, br, 1H), 1.14 (t, J=8 Hz, 3H), 1.92-1.94(m, 2H), 2.08 (dd, J=4, 12 Hz, 1H), 2.18 (m, 1H), 2.55 (t, J=12 Hz, 1H),2.86 (d, J=16 Hz, 1H), 3.03 (s, br, 1H), 3.12 (d, J=16 Hz, 1H), 3.43 (s,br, 1H), 3.48 (s, 3H), 3.63 (m, 1H), 4.41 (s, br, 1H), 5.09 (d, J=12 Hz,1H), 7.14 (m, 2H), 7.30 (s, 1H), 7.32 (m, 3H), 7.46 (s, br, 2H); MassSpectrum (ESI) m/z=552.2 (M+1).

Examples 336 to 339 were prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3-methylbutan-2-yl)-3-methylpiperidin-2-one(Example 261, Step H) by procedures similar to the one described inExample 300, replacing benzenethiol with the designated reagent.

Example R Reagent used 336

2,2,2-trifluoroethanethiol 337 ^(t)Bu— 2-methylpropane-2-thiol 338 Metrimethylsilylmethanethiol (as per Example 301)

Example 3362-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl-1-((2,2,2-trifluoroethyl)sulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.52 (s, 3 H), 0.67 (s, 3 H), 1.35(br s, 3 H), 2.07 (dd, J=13.7, 2.9 Hz, 1 H), 2.19 (dq, J=14.4, 7 Hz, 1H), 2.27 (t, J=13.7 Hz, 1 H), 2.61 (d, J=13.5 Hz, 1 H), 2.99 (d, J=13.5Hz, 1 H), 3.26-3.30 (m, 1 H), 3.41 (dd, J=13.8, 1.6 Hz, 1 H), 3.58 (ddd,J=13.7, 11, 2.9 Hz, 1 H), 4.24 (dd, J=13.9, 10.5 Hz, 1 H), 4.36-4.60 (m,2 H), 4.99-5.07 (m, 1 H), 6.95-7.01 (m, 1 H), 7.01-7.05 (m, 1H),7.08-7.16 (m, 3 H), 7.17-8.26 (m, 3 H); Mass Spectrum (ESI) m/z=608(M+H)

Example 3372-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)-3-methylbutan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.51 (d, J=6.9 Hz, 3 H), 0.65 (d,J=6.6 Hz, 3 H), 1.37 (s, 3 H), 1.45 (s, 9 H), 2.01-2.10 (m, 1 H),2.11-2.25 (m, 1 H), 2.30 (t, J=13.7 Hz, 1 H), 2.61 (d, J=13.5 Hz, 1 H),2.99 (d, J=13.7 Hz, 1 H), 3.10 (dd, J=13.7, 1.71 Hz, 1 H), 3.25-3.29 (m,1 H), 3.57 (ddd, J=13.6, 11.1, 2.9 Hz, 1 H), 3.96 (dd, J=13.8, 10.4 Hz,1 H), 5.15 (d, J=11.3 Hz, 1 H), 6.98-7.03 (m, 1 H), 7.04-7.17 (m, 3 H),7.18-8.01 (m, 3 H); Mass Spectrum (ESI) m/z=582.2 (M+H).

Example 3382-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-3-methyl-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.50 (d, J=6.9 Hz, 3 H), 0.67 (d,J=6.6 Hz, 3 H), 1.37 (s, 3 H), 2.05 (dd, J=13.8, 3.1 Hz, 1 H), 2.18 (dq,J=14.2, 6.9 Hz, 1 H), 2.29 (t, J=13.6 Hz, 1 H), 2.62 (d, J=13.5 Hz, 1H), 2.99 (d, J=13.5 Hz, 1 H), 3.09 (br s, 3 H), 3.20-3.29 (m, 1 H),3.32-3.35 (m, 1 H), 3.56 (ddd, J=13.8, 10.9, 2.9 Hz, 1 H), 4.07 (dd,J=13.9, 10.5 Hz, 1 H), 5.09 (d, J=11 Hz, 1 H), 6.98 (dt, J=7.2, 1.4 Hz,1 H), 7.03-7.08 (m, 1 H), 7.08-7.16 (m, 2 H), 7.29 (br s, 4 H); MassSpectrum (ESI) m/z=540.2 (M+H).

Example 3392-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtrifluoromethanesulfonate

By the method of Example 361 Step A using (S)-2-aminobutanol in place ofL-valinol, the title compound was obtained as the first elutingdiastereomer.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.95 (1 H, br. s), 7.34-7.60 (2 H, m),7.18-7.34 (4 H, m), 7.13 (1 H, dt, J=7.5, 1.3 Hz), 5.88 (1 H, m), 5.37(1 H, dd, J=16.8, 1.6 Hz), 5.28 (1 H, dd, J=10.0, 2.0 Hz), 5.16 (1 H, d,J=10.8 Hz), 5.06 (1 H, t, J=9.8 Hz), 4.78 (1 H, dd, J=9.5, 7.1 Hz), 4.45(1H, m, J=2.7 Hz), 3.88-3.98 (1 H, m), 2.66-2.85 (2 H, m), 2.33 (1 H, t,J=13.4 Hz), 1.99 (1 H, dd, J=13.7, 3.4 Hz), 1.32 (3 H, s), 0.94 (1 H,m), 0.59 (3 H, t, J=7.2 Hz), 0.41-0.53 (1 H, m); Mass Spectrum (ESI)m/z=428.2 (M⁺).

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylthio)butan-2-yl)-3-methylpiperidin-2-one

To a solution of(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtrifluoromethanesulfonate (86 mg, 0.15 mmol; Example 339, Step A) in DMF(0.74 ml) was added sodium ethanethiolate (38 mg, 0.45 mmol). Afterbeing stirred at 25° C. for 1.5 h, the reaction was quenched (sat. aq.NH₄Cl), extracted (2×EtOAc), and washed (2×brine). The combined organiclayers were dried over Na₂SO₄, filtered and the filtrate wasconcentrated under reduced pressure. Purification of the residue bychromatography on silica gel (12 g SiO₂, 10% and 20% EtOAc/hex) providedthe title compound as a colorless liquid.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a rapidly stirring solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylthio)butan-2-yl)-3-methylpiperidin-2-one(60 mg, 0.12 mmol; Example 339, Step B) in a mixture of water (0.66 mL),acetonitrile (0.44 mL), and CCl₄ (0.44 mL) was added sodium periodate(157 mg, 0.734 mmol), followed by ruthenium(III) chloride hydrate (2.8mg, 0.012 mmol). After being vigorously stirred for 5 h, the reactionwas acidified (10% citric acid) and diluted (EtOAc). The reactionmixture was filtered through a pad of Celite® (J.T. Baker, Phillipsberg,N.J., diatomaceous earth) and the filtrate was extracted (2×EtOAc). Thecombined organic layers were washed with brine, dried over Na₂SO₄filtered and the filtrate was concentrated under reduced pressure.Purification of the residue by reverse phase preparatory HPLC (Gemini™Prep C₁₈ 5 μm column, Phenomenex, Torrance, Calif.; gradient elution of40% to 60% MeCN in water, where both solvents contain 0.1% TFA) providedthe title compound as a white foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.24-7.26 (2 H, m), 7.01-7.20 (4 H,m), 6.93-6.98 (1 H, m), 6.85 (1 H, d, J=7.0 Hz), 4.94 (1 H, d, J=10.6Hz), 4.15 (1 H, t, J=12.1 Hz), 3.24-3.37 (1 H, m), 2.92-3.18 (4 H, m),2.71-2.82 (2 H, m), 2.38 (1 H, t, J=13.8 Hz), 2.06-2.21 (1 H, m), 1.92(1 H, dd, J=13.7, 2.7 Hz), 1.48 (3 H, s), 1.42-1.46 (1 H, m) 1.44 (3 H,t, J=7.5 Hz), 0.41 (3 H, t, J=7.5 Hz); Mass Spectrum (ESI) m/z=540.1[M+H.

Example 3402-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methylpiperidin-2-one

To a solution of(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtrifluoromethanesulfonate (75 mg, 0.130 mmol; Example 339, Step A) inacetonitrile (1.3 mL) was added cyclopropanesulfinic acid sodium salt(50 mg, 0.39 mmol) at 25° C. After being stirred at 90° C. for 1 day,the reaction was quenched with sat. aq. NH₄Cl solution, extracted(2×EtOAc) and the combined organic layers wer washed with brine (2×),dried over Na₂SO₄, filtered and the filtrate was concentrated underreduced pressure. Purification of the residue by chromatography onsilica gel (12 g SiO₂, 35% and 45% EtOAc/hex) provided the titlecompound as a colorless liquid.

Step B.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methylpiperidin-2-one(Example 340, Step A) by a procedure similar to the one described inExample 339 Step C.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.26 (2 H, m), 6.99-7.19 (4 H,m), 6.91-6.97 (1 H, m), 6.76-6.89 (1 H, m), 4.91 (1 H, d, J=10.8 Hz),4.21 (1 H, dd, J=13.5, 11.3 Hz), 3.31 (1 H, t, J=10.3 Hz), 3.12 (1 H,ddd, J=13.6, 10.9, 2.6 Hz), 2.88-3.02 (2 H, m), 2.76 (1 H, d, J=14.9Hz), 2.31-2.49 (2 H, m), 2.06-2.24 (1H, m), 1.90 (1H, dd, J=13.7, 2.7Hz), 1.40-1.56 (1 H, m), 1.47 (3H, s), 1.23-1.36 (2 H, m), 1.01-1.16 (2H, m), 0.42 (3 H, t, J=7.5 Hz); Mass Spectrum (ESI) 552.2 [M+H]⁺.

Examples 340 and 341 were prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtrifluoromethanesulfonate (Example 339, Step A) by a procedure similarto the one described in either Example 339 or Example 340, using anequivalent amount of the appropriate reagent in step B.

Example R Method Reagent used 341

Example 339 propane-2-thiolate, prepared in situ from cesium carbonate(206 mg, 0.63 mmol) and 2-propanethiol (59 μl, 0.63 mmol) 342

Example 339 2-methylpropanethiolate, prepared in situ from2-methylpropane-2-thiol (113 μl, 1.00 mmol) and sodium carbonate (106mg, 1.00 mmol) 343

Example 340 cyclobutanesulfinic acid, sodium salt,

Example 3412-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22-7.26 (2 H, br s), 7.02-7.21 (4H, m), 6.92-6.94 (1 H, s), 6.85 (1 H, d, J=7.0 Hz), 4.97 (1 H, d, J=10.8Hz), 4.10 (1 H, t, J=11.7 Hz), 3.27-3.42 (1 H, m), 2.98-3.16 (3 H, m),2.70-2.78 (2 H, m), 2.40 (1 H, t, J=13.9 Hz), 2.08-2.26 (1 H, m),1.86-1.93 (1 H, s), 1.49 (3 H, s), 1.43 (3 H, d, J=6.8 Hz), 1.43 (3 H,d, J=6.8 Hz), 1.40-1.50 (1 H, m) 0.41 (3 H, t, J=7.5 Hz); Mass Spectrum(ESI) m/z=554.2 [M+H]⁺.

Example 3422-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.21-7.26 (2 H, m), 7.01-7.20 (4 H,m), 6.92-6.94 (1 H, m), 6.85 (1 H, d, J=7.1 Hz), 4.99 (1 H, d, J=10.8Hz), 4.04 (1 H, dd, J=13.2, 11.2 Hz), 3.33 (1 H, t, J=10.4 Hz),3.03-3.15 (2 H, m), 2.80 (1 H, dd, J=13.2, 2.0 Hz), 2.72 (1 H, d, J=15.4Hz), 2.43 (1 H, t, J=13.8 Hz), 2.08-2.23 (1 H, m), 1.86 (1 H, dd,J=13.7, 2.4 Hz), 1.50 (3 H, s), 1.46-1.49 (1H, m), 1.44 (9 H, s), 0.41(3 H, t, J=7.6 Hz); Mass Spectrum (ESI) 568.2 [M+H]⁺.

Example 3432-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.21-7.27 (2 H, m), 7.00-7.21 (4 H,m), 6.93-6.97 (1 H, s), 6.86 (1 H, d, J=7.1 Hz), 4.97 (1 H, d, J=10.8Hz), 3.98 (1 H, t, J=12.2 Hz), 3.76 (1 H, quin, J=8.3 Hz), 3.31 (1 H, t,J=9.9 Hz), 3.12 (1 H, ddd, J=13.6, 10.9, 2.7 Hz), 2.99 (1 H, d, J=14.9Hz), 2.75 (1 H, d, J=14.9 Hz), 2.50-2.69 (3 H, m), 2.27-2.46 (3 H, m),2.04-2.19 (3 H, m), 1.91 (1 H, dd, J=13.7, 2.7 Hz), 1.48-1.52 (3 H, m),1.41-1.47 (1 H, m), 0.40 (3 H, t, J=7.6 Hz); Mass Spectrum (ESI) 566.2[M+H]⁺.

Synthesis of cyclobutanesulfinic acid, sodium salt

The reagent was prepared by procedures similar to the ones described inWO2007/14011 and WO2010/39982. To a suspension of magnesium (306 mg,12.6 mmol) in ether (7.4 mL) was added a solution of bromocyclobutane(1.00 g, 7.41 mmol) in ether (7.4 mL) in several small portions at 25°C. After the initial exotherm had ceased, the mixture was further heatedto reflux for 1 h. Then the suspension was added in small portions to anice cold solution of sulfuryl dichloride (3.00 g, 22.2 mmol) in DCM (12mL). The suspension was warmed to room temperature and the volatileswere removed under reduced pressure. The residue was dried under avacuum, then extracted with hexane (80 mL). The hexane suspension wasfiltered and the filter cake was washed with hexanes. The combinedfiltrates were dried (Na₂SO₄) and concentrated under reduced pressure togive crude cyclobutanesulfonyl chloride. The crude cyclobutanesulfonylchloride (1.15 g, 7.44 mmol) was added to a suspension of sodium sulfite(2.16 g, 17.1 mmol) in water (9.7 ml) and sodium carbonate (1.42 g, 13.4mmol). The resulting solution was heated to reflux for 1 h. The reactionwas cooled and lyophilized to remove water. Ethanol (50 mL) was added tothe residue, and the resulting mixture was heated under reflux for 2 h.The mixture was filtrered. The filtrate was concentrated under thereduced pressure to give the crude title compound which was used as isin the next step.

Example 3442-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(ethylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3,8-diethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(300 mg, 0.652 mmol) (Example 202, Step B) in DCM (6 mL) was addedtriethylamine (270 μl, 1.955 mmol) and methanesulfonic anhydride (170mg, 0.977 mmol) successively at 0° C. The reaction was allowed to warmto rt. After being stirred at rt for 2 h, the reaction was quenched with10% aq. citric acid, extracted with DCM and the combined extracts werewashed with water, dried over Na₂SO₄, filtered and the filtrate was andconcentrated to give the title compound.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(ethylthio)butan-2-yl)piperidin-2-one

The title compound was prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3,8-diethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (Example 344, step A) by a procedure similar to the onedescribed in Example 339, step B.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(ethylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(ethylthio)butan-2-yl)piperidin-2-one(Example 344, step B) by a procedure similar to the one described inExample 339, step C.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 (t, J=8.0 Hz, 3 H), 0.97 (t,J=8.0 Hz, 3 H), 1.44 (s, 3 H), 1.50 (m, 1 H), 1.86 (dd, J=12, 4 Hz, 1H), 1.97 (m, 2 H), 2.15 (m, 1 H), 2.36 (t, J=12 Hz, 1 H), 2.79 (m, 1 H),2.81 (d, J=16 Hz, 1 H), 2.92 (d, J=16.0 Hz, 1 H), 3.04 (m, 2 H), 3.16(m, 1 H), 3.19 (m, 1 H), 4.11 (m, 1 H), 4.97 (d, J=12 Hz, 1 H), 6.86 (d,J=8.0 Hz, 1 H), 6.97 (s, 1 H), 7.13 (m, 3 H), 7.38 (m, 3 H); MassSpectrum (ESI) m/z=554.0 [M+H]⁺.

Examples 345 to 347 were prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3,8-diethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (Example 344, Step A) by a procedure similar to the onedescribed in either Example 339 or Example 340, using an equivalentamount of the appropriate reagent in step B.

Example R Method Reagent used 345

Example 339 propane-2-thiolate, prepared in situ from cesium carbonate(206 mg, 0.63 mmol) and 2-propanethiol (59 μl, 0.63 mmol) 346

Example 339 2-methylpropanethiolate, prepared in situ from2-methylpropane-2-thiol (113 μl, 1.00 mmol) and sodium carbonate (106mg, 1.00 mmol) 347

Example 340 cyclobutanesulfinic acid sodium salt, prepared as describedin Example 343 348

Example 340 cyclopropanesulfinic acid sodium salt, prepared by themethod as described in Example 343

Example 3452-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-1-((S)-1-(isopropylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.40 (t, J=8.0 Hz, 3 H), 0.97 (t,J=8.0 Hz, 3 H), 1.43 (d, J=4 Hz, 6 H), 1.50 (m, 1 H), 1.86 (dd, J=12, 4Hz, 1 H), 1.98 (m, 2 H), 2.19 (m, 1 H), 2.37 (t, J=12 Hz, 1 H), 2.73 (d,J=12 Hz, 1 H), 2.79 (d, J=12.0 Hz, 1 H), 2.97 (d, J=12 Hz, 1 H), 3.10(m, 2 H), 3.37 (m, 1 H), 4.09 (m, 1H), 4.99 (d, J=12 Hz, 1 H), 6.86 (d,J=8.0 Hz, 1 H), 6.98 (s, 1 H), 7.12 (m, 4 H), 7.27 (m, 2 H); MassSpectrum (ESI) m/z=568.0 [M+H]⁺.

Example 3462-((3R,5R,6S)-1-((S)-1-(tert-butylsulfonyl)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39 (t, J=8.0 Hz, 3 H), 0.97 (t,J=8.0 Hz, 3 H), 1.43 (s, 9 H), 1.50 (m, 1 H), 1.85 (dd, J=12, 4 Hz, 1H), 1.97 (m, 2 H), 2.15 (m, 1 H), 2.38 (t, J=12 Hz, 1 H), 2.80 (d, J=16Hz, 1 H), 2.96 (d, J=16.0 Hz, 1 H), 3.14 (m, 2 H), 3.35 (m, 1 H), 4.01(m, 1 H), 5.02 (d, J=8 Hz, 1 H), 6.87 (d, J=8.0 Hz, 1 H), 6.98 (s, 1 H),7.13 (m, 4 H), 7.38 (m, 2 H); Mass Spectrum (ESI) m/z=582.1 [M+H]⁺.

Example 3472-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclobutylsulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39 (t, J=8.0 Hz, 3 H), 0.98 (t,J=8.0 Hz, 3 H), 1.50 (m, 1 H), 1.84-2.45 (m, 6 H), 2.38 (m, 3 H), 2.62(m, 3 H), 2.80 (d, J=16 Hz, 1 H), 2.94 (d, J=16.0 Hz, 1 H), 3.15 (d,J=12 Hz, 1H), 3.34 (m, 1 H), 3.76 (m, 1 H), 3.94 (m, 1 H), 5.00 (d, J=12Hz, 1 H), 6.87 (d, J=8.0 Hz, 1 H), 6.98 (s, 1 H), 7.13 (m, 3 H), 7.28(m, 3 H); Mass Spectrum (ESI) 580.0 [M+H]⁺.

Example 3482-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.42 (t, J=8.0 Hz, 3 H), 0.97 (t,J=8.0 Hz, 3 H), 1.10 (m, 2 H), 1.26 (m, 2 H), 1.52 (m, 1 H), 1.83 (dd,J=16, 4 Hz, 1 H), 1.96 (m, 2 H), 2.14 (m, 1 H), 2.34 (d, J=16.0 Hz, 1H), 2.42 (m, 1 H), 2.79 (d, J=12 Hz, 1 H), 2.95 (m, 1 H), 2.98 (d, J=16Hz, 1 H), 3.12 (m, 1 H), 3.34 (m, 1 H), 4.15 (m, 1 H), 5.00 (d, J=12 Hz,1 H), 6.84 (d, J=8.0 Hz, 1 H), 6.96 (s, 1 H), 7.12 (m, 4 H), 7.27 (m, 2H); Mass Spectrum (ESI) m/z=566.0 [M+H]⁺.

Example 3492-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 252, Step A) by a procedure similar to the one described inExample 344, step A.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylthio)ethyl)-3-methylpiperidin-2-one

The title compound was prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (Example 349, Step A) and sodium ethanethiolate asdescribed in Example 339.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylthio)ethyl)-3-methylpiperidin-2-one(Example 349, step B) by a procedure similar to the one described inExample 339, step C.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.26 (3 H, m), 7.07-7.17 (3 H,m), 6.95-6.98 (1 H, m), 6.82-6.88 (1 H, m), 4.90 (1 H, d, J=10.6 Hz),4.25-4.46 (1 H, m), 3.11-3.24 (1 H, m), 2.99-3.09 (3 H, m), 2.92 (1H, d,J=12.1 Hz), 2.80 (1 H, d, J=14.7 Hz), 2.64-2.77 (1 H, m), 2.42 (1 H, t,J=13.8 Hz), 1.91 (1 H, dd, J=13.9, 2.5 Hz), 1.83 (1 H, br. s.), 1.49 (3H, s), 1.44 (3 H, t, J=7.5 Hz), 0.32-0.42 (1 H, m), 0.18-0.27 (1 H, m),−0.35-−0.24 (1 H, m), −1.15-−0.95 (1 H, m); Mass Spectrum (ESI) 552.2[M+H]⁺.

Examples 350 to 356 were prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (Example 349, Step A) by a procedure similar to the onedescribed in either Example 339 or Example 340, using an equivalentamount of the appropriate reagent in step B.

Example R Method Reagent used 350

Example 339 propane-2-thiolate, prepared in situ from 2-propanethiol andsodium carbonate 351

Example 339 2-methylpropanethiolate, prepared in situ from2-methylpropane-2-thiol and sodium carbonate 352

Example 340 cyclobutanesulfinic acid sodium salt, prepared as describedin Example 343 353

Example 340 cyclopropanesulfinic acid sodium salt, prepared by themethod as described in Example 343 354 Me Example 340 sodiummethanesulfinate 355

Example 339 2-methylbutane-2-thiolate, prepared in situ from2-methylbutane-2-thiol and NaH 356

Example 339 2,4-di-fluorobenzenethiolate prepared in situ from2,4-di-fluorobenzenethiol and NaH

Example 3502-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(isopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23-7.26 (3 H, m), 7.04-7.20 (3 H,m), 6.93-6.97 (1 H, m), 6.84-6.88 (1 H, m), 4.93 (1 H, d, J=10.8 Hz),4.34 (1 H, br. s.), 3.05-3.18 (3 H, m), 2.86 (1 H, d, J=13.3 Hz), 2.77(2 H, d, J=15.3 Hz), 2.46 (1 H, t, J=13.8 Hz), 1.86 (2 H, dd, J=13.5,2.5 Hz), 1.51 (3 H, s), 1.44 (6 H, d, J=6.8 Hz), 0.31-0.44 (1 H, m),0.18-2.80 (1 H, m), −0.35-−0.23 (1 H, m), −1.15-−1.02 (1 H, br. s.);Mass Spectrum (ESI) 566.2 [M+H]⁺.

Example 3512-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.26 (3 H, m), 7.03-7.17 (3 H,m), 6.93-6.97 (1 H, m), 6.82-6.92 (1 H, m), 4.95 (1 H, d, J=10.6 Hz),4.30 (1 H, t, J=12.0 Hz), 3.14 (1 H, ddd, J=13.6, 10.8, 2.6 Hz), 3.07 (1H, d, J=15.1 Hz), 2.92 (1 H, d, J=11.9 Hz), 2.79 (1 H, d, J=15.1 Hz),2.72 (1H, t, J=9.6 Hz), 2.45 (1 H, t, J=13.8 Hz), 1.88 (2 H, dd, J=13.6,2.4 Hz), 1.50 (3 H, s), 1.44 (9 H, s), 0.30-0.44 (1 H, m), 0.17-0.30 (1H, m), −0.37-−0.26 (1 H, m), −1.15-−1.05 (1 H, m); Mass Spectrum (ESI)580.2 [M+H]⁺.

Example 3522-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-2-(cyclobutylsulfonyl)-1-cyclopropylethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.27 (3 H, m), 7.07-7.15 (3 H,m), 6.94-6.98 (1 H, m), 6.84-6.93 (1 H, m), 4.93 (1 H, d, J=10.6 Hz),4.23 (1 H, t, J=11.3 Hz), 3.77 (1 H, quin, J=8.3 Hz), 3.12-3.22 (1 H,m), 3.08 (1 H, d, J=15.1 Hz), 2.70-2.83 (3 H, m), 2.53-2.69 (2 H, m),2.47 (1H, t, J=13.8 Hz), 2.27-2.40 (2 H, m), 2.04-2.19 (2 H, m),1.73-1.97 (2 H, m), 1.51 (3 H, s), 0.30-0.41 (1 H, m), 0.20-0.30 (1 H,m), −0.35-−0.25 (1 H, m), −1.12-−0.95 (1 H, m); Mass Spectrum (ESI)578.1 [M+H]⁺.

Example 3532-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(cyclopropylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18-7.26 (3 H, m), 7.06-7.15 (3 H,m), 6.92-6.97 (1 H, m), 6.82-6.88 (1 H, m), 4.87 (1 H, d, J=10.6 Hz),4.44 (1 H, br. s.), 3.11-3.23 (1 H, m), 3.01-3.10 (2 H, m), 2.78 (1 H,d, J=15.1 Hz), 2.73 (1 H, br. s.), 2.35-2.47 (2 H, m), 1.88 (1 H, dd,J=13.8, 2.6 Hz), 1.76-1.85 (1 H, m), 1.49 (3 H, s), 1.24-1.35 (2 H, m),1.03-1.16 (2 H, m), 0.32-0.44 (1 H, m), 0.20-0.30 (1 H, m), −0.33-−0.21(1 H, m), −1.02-−0.98 (1 H, br. s.); Mass Spectrum (ESI) 564.1 [M+H]⁺.

Example 3542-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(methylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.03 (br s, 1 H)-0.26 (br s, 1 H)0.27 (br s, 1 H) 0.33-0.49 (m, 1 H) 1.51 (s, 3 H) 1.71-1.97 (m, 2 H)2.43 (t, J=13.79 Hz, 1 H) 2.78 (m, 2 H) 3.00 (s, 3 H) 3.01-3.24 (m, 3 H)4.44 (br s, 1 H) 4.87 (d, J=10.56 Hz, 1 H) 6.81-6.92 (m, 1 H) 6.96 (s, 1H) 7.07-7.20 (m, 2 H) 7.27 (m, 4 H); Mass Spectrum (ESI) m/z=540 (M+1).

Example 3552-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(tert-pentylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.11 (br s, 1H), −0.31 (br s, 1H),0.23 (br s, 1H), 0.36 (br s, 1H), 1.04 (t, J=7.53 Hz, 3H), 1.28-1.44 (m,6H), 1.50 (s, 3H), 1.73-1.95 (m, 4H), 2.48 (t, J=13.89 Hz, 1H), 2.76 (d,J=15.26 Hz, 2H), 2.91 (d, J=13.11 Hz, 1H), 3.04-3.23 (m, 2H), 4.28 (t,J=11.15 Hz, 1H), 4.90-5.07 (m, 1H), 6.84-6.93 (m, 1H), 6.94-7.03 (m,1H), 7.05-7.37 (br s, 6H); Mass Spectrum (ESI) m/z=594.0 (M+1).

Example 3562-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((2,4-difluorophenyl)sulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.06 (br s, 1H), −0.29 (br s, 1H),0.15-0.28 (m, 1H), 0.28-0.44 (m, 1H), 1.37 (s, 1H), 1.54 (s, 3H),1.77-1.95 (m, 2H), 2.48 (t, J=13.79 Hz, 1H), 2.67-2.85 (m, 1H), 3.07 (d,J=14.87 Hz, 1H), 3.13-3.32 (m, 2H), 4.65 (br s, 1H), 4.92 (d, J=10.56Hz, 1H), 6.81-6.94 (m, 2H), 6.94-7.21 (m, 8H), 7.99 (td, J=8.31, 6.06Hz, 1H); MS (ESI) m/e=636.0 (M+1).

Example 3572-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-ethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-ethylpiperidin-2-one(Example 253, Step C) by a procedure similar to the one described inExample 344, step A.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylthio)ethyl)-3-ethylpiperidin-2-one

The title compound was prepared from(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-ethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (Example 357, Step A) and sodium ethanethiolate by themethod described in Example 339.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylthio)ethyl)-3-ethylpiperidin-2-one(Example 357, step B) by a procedure similar to the one described inExample 339, step C.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.99 (br s, 1 H)-0.25 (br s, 1 H)0.30 (br s, 1 H) 0.40 (br s, 1 H) 0.98 (t, J=7.46 Hz, 3 H) 1.44 (t,J=7.58 Hz, 3 H) 1.83 (m, 2 H) 1.92-2.09 (m, 2 H) 2.41 (t, J=13.69 Hz, 1H) 2.71-2.88 (m, 2 H) 2.94 (d, J=13.45 Hz, 1 H) 3.00-3.20 (m, 4 H) 4.30(br. s, 1 H) 4.92 (d, J=10.76 Hz, 1 H) 6.81-6.87 (m, 1 H) 6.97 (m, 1 H)7.08-7.26 (m, 3 H); 7.30-7.50 (m, 4H); Mass Spectrum (ESI) m/z=566(M+1).

Examples 358 to 360 were prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-ethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (Example 357, Step A) by a procedure similar to the onedescribed in either Example 339 or Example 340, using an equivalentamount of the appropriate reagent in step B.

Example R Method Reagent used 358

Example 339 propane-2-thiolate, prepared in situ from 2-propanethiol andNaH 359

Example 339 2-methylpropanethiolate, prepared in situ from2-methylpropane-2-thiol and NaH 360

Example 340 cyclopropanesulfinate

Example 3582-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(isopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.01 (br s, 1H), −0.27 (br s, 1H),0.29 (br s, 1H), 0.39 (br s, 1H), 0.98 (t, J=7.53 Hz, 3H), 1.33-1.52 (m,6H), 1.71-1.94 (m, 2H), 2.01 (q, J=7.43 Hz, 2H), 2.42 (t, J=13.79 Hz,1H), 2.70-2.95 (m, 3H), 2.99-3.24 (m, 3H), 4.28 (br s, 1H), 4.95 (d,J=10.56 Hz, 1H), 6.83-6.94 (m, 2H), 6.94-7.05 (m, 2H), 7.05-7.21 (m,4H); MS (ESI) m/z=580.0 and 581.9 (M+1).

Example 3592-((3R,5R,6S)-1-((S)-2-(tert-Butylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −1.05 (br s, 1 H)-0.29 (br s, 1 H)0.27 (br s, 1 H) 0.34-0.42 (m, 1 H) 0.98 (t, J=7.46 Hz, 3 H) 1.44 (s, 9H) 1.81 (dd, J=13.69, 2.93 Hz, 1 H) 1.87-2.11 (m, 3 H) 2.43 (t, J=13.82Hz, 1 H) 2.79 (d, J=15.89 Hz, 2 H) 2.95 (d, J=13.20 Hz, 1 H) 3.04-3.19(m, 2 H) 4.21 (m, 1 H) 4.97 (d, J=10.76 Hz, 1 H) 6.75-6.92 (m, 2 H)6.92-7.01 (m, 1 H) 7.06-7.17 (m, 3 H) 7.43 (m, 2 H); Mass Spectrum (ESI)m/z=594 (M+1).

Example 3602-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(cyclopropylsulfonyl)ethyl)-3-ethyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm −0.99 (br s, 1 H)-0.25 (br s, 1 H)0.29 (br s, 1 H) 0.36-0.45 (m, 1 H) 0.97 (t, J=7.46 Hz, 3 H) 1.07-1.16(m, 2 H) 1.21-1.34 (m, 2 H) 1.82 (dd, J=13.69, 2.93 Hz, 1 H) 1.86-1.92(m, 1 H) 1.92-2.14 (m, 2 H) 2.36-2.46 (m, 2 H) 2.80 (d, J=15.65 Hz, 1 H)3.03-3.16 (m, 3 H) 4.34 (m, 1H) 4.90 (d, J=10.51 Hz, 1 H) 6.80-6.89 (m,1 H) 6.92-6.99 (m, 1 H) 7.06-7.17 (m, 3 H) 7.35-7.45 (m, 3 H); MassSpectrum (ESI) m/z=578 (M+1).

Example 3612-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtrifluoromethanesulfonate

L-valinol (Sigma Aldrich, St. Louis, Mo.) (3.64 g), racemic(3S/R,5R/S,6R/S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one(3.17 g; Example 261, step E) and lithium t-butoxide (0.025 g) wereheated as a melt for 17 hr using an oil bath set at 135° C. Aftercooling, the glassy solid was dissolved in dichloromethane. The organiclayer was washed with sat ammonium chloride solution followed by 1Nsodium hydroxide solution and then brine. The organic layer was driedover magnesium sulfate and concentrated to give 3.88 g of a mixture ofdiastereomers. A 2.61 g portion (67% of total) of the ca. 1:1 mixtureobtained above was dissolved in toluene and evaporated to dryness threetimes to remove residual moisture. Dichloromethane (55 ml) and2,6-dimethylpyridine (3.3 ml, 28 5 mmol) were added and the resultingstirred solution was cooled to −50° C. in a dry ice/acetonitrile bath.Trifluoromethanesulfonic anhydride (2.4 ml, 14.27 mmol) was added overthe course of 10 minutes such that the internal temperature neverexceeded −45° C. After 40 min, the reaction was quenched by addition of2 M HCl. The mixture was warmed to room temperature, diluted indichloromethane, washed with 2 N HCl, water, and finally brine. Theorganics were dried over magnesium sulfate, filtered, and concentratedto a yellow foam that weighed ca. 2.6 g. A portion of this material(1.92 g, 74%) was purified by medium-pressure liquid chromatographyusing a 120 g column, eluting with a gradient of 20 to 100% acetone inhexanes. Fractions containing the faster-eluting (less polar)diastereomer were concentrated to give the title compound as a whitefoam.

¹H NMR (400 MHz, CDCl₃) δ ppm 0.62 (d, J=2.4 Hz, 3 H), 0.64-0.74 (m, 4H), 1.51 (s, 3H), 2.04 (dd, J=14.1, 3.5 Hz, 1 H), 2.54-2.79 (m, 3 H),3.58 (ddd, J=13.7, 10.8, 3.5 Hz, 1H), 4.59 (dd, J=10.2, 4.7 Hz, 1H),4.67 (dd, J=9.2, 4.9 Hz, 1 H), 5.23-5.45 (m, 3 H), 5.71 (d, J=11 Hz, 1H), 5.83 (ddt, J=17, 9.9, 7.4 Hz, 1 H), 7.06 (t, J=1.8 Hz, 1 H),7.11-7.16 (m, 1 H), 7.19 (t, J=7.7 Hz, 1 H), 7.23-7.32 (m, 3 H), 7.39(br s, 2 H); Mass Spectrum (ESI) m/z=442.2 (M⁺).

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtrifluoromethanesulfonate (Example 361, step A) by procedures similar tothe ones described in Example 339, using an equivalent amount ofethanethiol in step B.

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.51 (d, J=7.1 Hz, 3 H), 0.66 (d,J=6.6 Hz, 3 H), 1.37 (s, 3 H), 1.41 (t, J=7.5 Hz, 3 H), 2.05 (dd,J=13.7, 2.9 Hz, 1 H), 2.18 (dq, J=14.2, 6.9 Hz, 1 H), 2.31 (t, J=13.7Hz, 1 H), 2.62 (d, J=13.7 Hz, 1 H), 3.00 (d, J=13.7 Hz, 1 H), 3.14-3.24(m, 3 H), 3.25-3.30 (m, 1 H), 3.57 (ddd, J=13.8, 10.9, 2.9 Hz, 1 H),4.02 (dd, J=13.9, 10.5 Hz, 1 H), 5.12 (d, J=11 Hz, 1 H), 7.00 (dt,J=7.3, 1.5 Hz, 1 H), 7.04-8.17 (m, 7 H); Mass Spectrum (ESI) m/z=554.2(M+1).

Example 3622-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-isopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtrifluoromethanesulfonate (Example 361, step A) by procedures similar tothe ones described in Example 339, using an equivalent amount ofpropane-2-thiol in step B.

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.50 (d, J=6.9 Hz, 3 H), 0.65 (d,J=6.6 Hz, 3H), 1.37 (s, 3 H), 1.41 (d, J=6.9 Hz, 6 H), 2.05 (dd, J=13.6,2.8 Hz, 1H), 2.18 (dq, J=14, 6.9 Hz, 1 H), 2.31 (t, J=13.7 Hz, 1 H),2.61 (d, J=13.5 Hz, 1 H), 2.99 (d, J=13.7 Hz, 1 H), 3.11 (d, J=13.7 Hz,1 H), 3.25-3.29 (m, 1 H), 3.32-3.37 (m, 1 H), 3.49-3.65 (m, 1 H), 4.01(dd, J=13.7, 10.5 Hz, 1 H), 5.13 (d, J=11 Hz, 1 H), 6.93-7.03 (m, 1 H),7.03-8.23 (m, 7 H); Mass Spectrum (ESI) m/z=568.0 (M+1).

Example 3632-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(S)-2-((2R,3R)-2-(3-Chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N—((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-2-methylpent-4-enamide

(S)-tert-leucinol (0.937 g, 7.99 mmol) and(3S,5R,6R)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one(1 g, 2.66 mmol; Example 261, Step F) were combined in a reaction flaskand heated to 100° C. After 2 d, the reaction mixture was cooled to RTand dissolved in ethyl acetate. The organic phase was washed with 3×10mL 1N HCl and 1×10 mL brine, dried over MgSO₄, filtered and concentratedto afford the title compound.

¹H-NMR (500 MHz, CDCl₃) δ 7.21-7.10 (series of m, 5H), 7.07 (t, J=1.7Hz, 1H), 6.97 (m, 2H), 6.87 (br d, J=7.6 Hz, 1H), 5.91 (br d, J=8.3 Hz,1H), 5.65 (ddt, J=17.4, 10.3, 7.3 Hz, 1H), 5.05 (dd, J=10.5, 2.0 Hz,1H), 4.77 (d, J=4.9 Hz, 1H), 3.77 (m, 2H), 3.42 (m, 1H), 3.02 (dt,J=7.6, 5.4 Hz, 1H), 2.42 (dd, J=13.9, 7.1 Hz, 1H), 2.23 (dd, J=14.7, 5.6Hz, 1H), 2.05 (dd J=13.7, 7.6 Hz, 1H), 1.87 (dd, J=14.4, 7.6 Hz, 1H),1.17 (s, 3H), 0.92 (s, 9H); Mass Spectrum (ESI) m/z=492.2 (M+1).

Step B.(3S,5S,6R,8S)-8-Allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtriflate

To a solution of(S)-2-((2R,3R)-2-(3-chlorophenyl)-3-(4-chlorophenyl)-3-hydroxypropyl)-N—((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-2-methylpent-4-enamide(Example 363, step A, 950 mg, 1.929 mmol) in DCM (19 mL) at −50° C. wasadded 2,6-lutidine (896 μl, 7.72 mmol) followed bytrifluoromethanesulfonic anhydride solution (1M DCM, 4.34 mL, 4.34mmol). The progress of the reaction was monitored by LC/MS. Anadditional charge of 450 uL (2 eq) 2,6-lutidine followed by 1.12 eqtriflic anhydride (2.16 mmol, 2.16 mL of 1M solution indichloromethane). The reaction was allowed to warm to 0° C. and thenpoured into sat. aq. CuSO₄ solution. To the mixture was added 100 mLethyl acetate. The layers were separated and the organic phase waswashed with sat. aq. CuSO₄. The combined organic layers wereconcentrated and purified by column chromatography on silica gel(eluent: 20 to 50% acetone in hexanes) to afford the title compound.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 7.80-7.42 (series of m, 3H), 7.38-7.28(series of m, 4H), 7.14 (d, J=7.6 Hz, 1H), 5.85 (ddt, J=17.2, 10.0, 7.3Hz, 1H), 5.61 (d, J=7.1 Hz, 1H), 5.37 (dd, J=16.9, 1.7 Hz, 1H), 5.22(dd, J=10.0, 7.0 Hz, 1H), 5.17 (t, J=9.7 Hz, 1H), 4.61 (dd, J=9.3, 6.9Hz, 1H), 3.92 (ddd, J=9.8, 7.6, 4.2 Hz, 1H), 2.71 (m, 2H), 2.23 (dd,J=14.2, 9.5 Hz, 1H), 2.10 (dd, J=14.2, 4.4 Hz, 1H), 1.08 (s, 3H), 0.62(s, 9H); Mass Spectrum (ESI) m/z=474.2 (M⁺).

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-3,3-dimethyl-1-(methylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5S,6R,8S)-8-allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium triflate (Example 363, Step B) by proceduressimilar to the ones described in Example 340, using an equivalent amountof sodium methanesulfinate in step B.

Example 3642-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5S,6R,8S)-8-allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtriflate (Example 363, Step B) by procedures similar to the onesdescribed in Example 340, using an equivalent amount of sodiumethanesulfinate in step B.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.13-7.60 (m, 4 H), 7.04-7.12 (m, 2H), 6.94-7.00 (m, 2 H), 5.90 (ddt, J=17.2, 9.8, 7.5 Hz, 1 H), 5.17-5.29(m, 2 H), 5.12 (d, J=11.0 Hz, 1 H), 4.27 (dd, J=13.2, 11.2 Hz, 1 H),3.56 (dd, J=11.0, 2.2 Hz, 1 H), 3.45 (ddd, J=13.8, 10.9, 3.2 Hz, 1 H),3.03-3.14 (m, 2 H), 2.78 (dd, J=13.2, 2.2 Hz, 1 H), 2.67 (ABX,J_(AB)=13.7 Hz, J_(AX)=8.1 Hz, 1 H), 2.61 (ABX J_(AB)=13.7 Hz,J_(Bx)=6.8 Hz, 1H) (m, 2 H), 2.27 (t, J=13.7 Hz, 1 H), 1.81 (dd, J=13.6,3.3 Hz, 1 H), 1.47 (t, J=7.5 Hz, 3 H), 1.25 (s, 3 H), 0.71 (s, 9 H);Mass Spectrum (ESI) m/z=550.2 (M+1).

Example 3652-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-3-methylpiperidin-2-one

To a solution of(3S,5S,6R,8S)-8-allyl-3-(tert-butyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iumtrifluoromethanesulfonate (290 mg, 0.478 mmol; Example 363, Step B) in1,2-dichloroethane (4.78 mL) was added 5 mL of sat. aq. NaHCO₃ solution.The reaction mixture was heated to 50° C. for 3 d. The reaction mixturewas poured into a separatory funnel and the aqueous layer was extractedwith dichloromethane. The combined organic layers were washed with sat.aq. NaHCO₃ solution, dried over MgSO₄, filtered and the filtrate wasconcentrated. Purification by column chromatography using 25-35% ethylacetate in hexanes on a 4 g silica gel column afforded the titlecompound.

¹H-NMR (500 MHz, DMSO-d6) δ ppm 7.50-7.05 (series of m, 7H), 6.97 (d,J=7.3 Hz, 1H), 5.87 (dddd, J=16.9, 10.0, 8.3, 6.6 Hz, 1H), 5.26 (br d,J=16.6 Hz, 1H), 5.14 (dd, J=10.0, 2.2 Hz, 1H), 4.76 (d, J=11.0 Hz, 1H),3.97 (td, J=10.3, 6.8 Hz, 1H), 2.51 (m, 2H), 2.76 (dd, J=9.5, 4.4 Hz),2.65 (dd, J=13.7, 8.3 Hz, 1H), 2.50 (m, obscured by solvent), 2.07 (t,J=13.5 Hz, 1H), 1.75 (dd, J=13.2, 3.0 Hz, 1H), 1.12 (s, 3H), 0.63 (s,9H); Mass Spectrum (ESI) m/z=474.2 (M+1).

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3,3-dimethylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxy-3,3-dimethylbutan-2-yl)-3-methylpiperidin-2-one(Example 365, step A) by a procedure similar to the one described inExample 300, replacing benzenethiol with the appropriate amount ofpropane-2-thiol.

¹H-NMR (500 MHz, DMSO-d₆) δ ppm 12.36 (s, 1H), 7.81 (br s, 1H), 7.48 (brs, 1H), 7.25 (br s, 1H), 7.22 (t, J=7.8 Hz, 1H), 7.15 (ddd, J=7.8. 2.0,0.7 Hz, 1H), 7.04 (t, J=1.7 Hz, 1H), 7.00 (br d, J=7.8 Hz, 1H), 5.05 (d,J=11.2 Hz, 1H), 3.90 (dd, J=13.7, 11.0, 2.6 Hz, 1H), 3.70 (ddd, J=13.7,11.0, 2.6 Hz, 1H), 3.45 (m, 2H), 3.12 (dd, J=13.4, 2.0, 1H), 2.97 (d,J=13.9 Hz, 1H), 2.52 (m, obscured by solvent), 2.14 (t, J=13.2 Hz, 1H),2.03 (dd, J=13.4 Hz, 1H), 1.32 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.6 Hz,3H), 1.23 (s, 3H), 0.62 (s, 9H); Mass Spectrum (ESI) m/z=582.2 (M+1).

Example 3662-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pentan-3-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-mercaptoethyl)-3-methylpiperidin-2-one

To a solution of(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (370 mg; Example 349, Step A) in DMF (1.6 mL) was addedsodium hydrogensulfide (105 mg, 1.88 mmol). After being stirred at rtovernight, the reaction was quenched (sat. aq. NH₄Cl solution),extracted (2×EtOAc) and the combined organics were washed with brine(3×). The combined organic layers were dried (Na₂SO₄) and concentratedunder the reduced pressure. Purification of the residue bychromatography on silica gel (24 g SiO₂, gradient elution of 10% to 40%EtOAc in hex) provided the title compound.

Step B.(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pentan-3-ylthio)ethyl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-mercaptoethyl)-3-methylpiperidin-2-one(49 mg, 0.10 mmol; Example 366, Step A) and 3-bromopentane (51 μl, 0.41mmol) in DMF (0.52 mL) was added 60% sodium hydride in mineral oil (17mg, 0.41 mmol) at 25° C. The reaction was stirred at 25° C. for 1 h andthen heated to 60° C. After being stirred at 60° C. overnight, thereaction was quenched (10% aq. citric acid), extracted (2×EtOAc), andwashed (3×brine). The combined organic layers were dried (Na₂SO₄) andconcentrated under reduced pressure. Purification of the residue bychromatography on silica gel (4 g SiO₂, 9% and 18% EtOAc/hex) providedthe title compound.

Step C.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pentan-3-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pentan-3-ylthio)ethyl)-3-methylpiperidin-2-one(Example 366, Step B) by procedures similar to the one described inExample 71, Step F.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.34 (3 H, m), 7.06-7.16 (3 H,m), 6.93-6.98 (1 H, s), 6.83-6.90 (1 H, m), 4.93 (1 H, d, J=10.6 Hz),4.35 (1 H, br, s), 3.05-3.20 (2 H, m), 2.65-2.92 (4 H, m), 2.46 (1H, t,J=13.8 Hz), 1.92-2.11 (2 H, m), 1.75-1.91 (4 H, m), 1.50 (3 H, s),1.06-1.19 (6 H, m), 0.32-0.42 (1 H, m), 0.18-0.28 (1 H, m), −0.35-−0.25(1 H, m), −1.12-−1.02 (1 H, m); Mass Spectrum (ESI) m/z=594.2 [M+H]⁺.

Example 3672-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid; more polar isomer

Step A. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylthio)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate

The above compound was obtained from methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 186, Step A, 187 mg, 0.391 mmol) and propane-2-thiol (119 mg,1.56 mmol) by a procedure similar to the one described in Example 300,Step A, using the appropriate amount of propanethiol and reacting for atotal of 3 h. Purification of the residue by chromatography on silicagel (12 g, SiO₂, 5% to 20% EtOAc/Hex) provided the title compound as apale yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (d, J=8.4 Hz, 2H), 7.05-7.18(m, 2H), 7.02 (t, J=1.7 Hz, 2H), 6.79 (td, J=1.4, 7.4 Hz, 1H), 4.66 (d,J=10.6 Hz, 1H), 3.70 (s, 3H), 3.41 (dd, J=11, 12.7 Hz, 1H), 3.16 (ddd,J=3.1, 10.6, 13.6 Hz, 1H), 2.82-2.94 (m, 2H), 2.67-2.79 (m, 2H), 2.57(dd, J=4.1, 12.9 Hz, 1H), 2.16-2.27 (m, 1H), 1.97-2.12 (m, 2H), 1.57(ddd, J=3.8, 7.8, 14. Hz, 1H), 1.41 (d, J=6.9 Hz, 3H), 1.29-1.34 (m,5H), 0.49 (d, J=15.3 Hz, 3H); Mass Spectrum (ESI) m/z=558.1 [M−H]⁻,560.1 [M+H]⁺.

Step B. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetateand methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate

3-Chlorobenzoperoxoic acid (45.4 mg, 0.203 mmol) was added to a solutionof methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylthio)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(136 mg, 0.253 mmol; Example 367, Step A) in DCM (3 mL) at 0° C. After 1h at 0° C. the reaction was monitored by LCMS (MS (ESI) 552.2 [M+H]⁺,554.0 [M−H]⁻) showing 60% conversion. At this time an additional 0.2 eq.of 3-chorobenzoperoxoic acid was added. The reaction was monitored againafter 2 hours showing 85% conversion and was quenched at this time withsat. aq. NaHCO₃ solution. The solution was extracted with EtOAc and thecombined organic layers were washed with brine dried over MgSO₄,filtered and the filtrate was concentrated. The residue was purified bychromatography on silica gel (12 g, SiO₂, 10-60% EtOAc/hexane, 50 min)to give the title compounds as a 2:1 mixture of diatereomers, as a paleyellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.20-7.29 (m, 4H), 7.20-7.26 (m,2H), 7.19-7.20 (m, 1H), 7.04-7.20 (m, 6H), 6.95-7.02 (m, 2H), 6.82-6.95(m, 2H), 4.75-4.90 (m, 1H), 3.62-3.74 (m, 5H), 3.37-3.48 (m, 1H),3.07-3.32 (m, 3H), 2.59-2.95 (m, 6H), 1.93-2.33 (m, 5H), 1.47-1.74 (m,3H), 1.22-1.42 (m, 17H), 0.79-0.95 (m, 2H), 0.37-0.56 (m, 4H); MassSpectrum (ESI) m/z=552.2 [M−H]⁻, 554.0 [M+H]⁺.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid; more polar isomer

To a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetateand methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(100 mg, 0.181 mmol, as a 2:1 mixture of isomers; Example 267, Step B)in MeOH/THF/H₂O (1 mL/2 mL/1 mL) was added lithium hydroxide (43.3 mg,1.810 mmol). The reaction mixture was allowed to stir for 18 h. Afterthis period, the reaction mixture was acidified with 1N HCl andextracted with EtOAc (3×10 mL). The organics were pooled, washed withbrine, dried (MgSO₄), filtered and concentrated in vacuo. The crudematerial was purified by reverse-phase preparative HPLC (Gemini™ PrepC₁₈ 5 mm column; Phenomenex, Torrance, Calif.; gradient elution of 25%to 55% MeCN in water, where both solvents contain 0.1% TFA, 30 minmethod) to provide one of the title compounds as the more polar isomer(t_(R)=21.45 min)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.22 (d, J=8.0 Hz, 2H), 7.00-7.17(m, 4H), 6.80-6.98 (m, 2H), 4.80 (d, J=10.8 Hz, 1H), 3.53-3.73 (m, 1H),3.11-3.30 (m, 2H), 2.68-3.00 (m, 4H), 1.97-2.29 (m, 3H), 1.40-1.54 (m,4H), 1.36 (d, J=6.9 Hz, 3H), 1.28 (d, J=6.9 Hz, 3H), 0.41 (t, J=7.5 Hz,3H); Mass Spectrum (ESI) 538.2 [M−H]⁻, 540.2 [M+H]⁺.

Further elution from Example 367 provided the less polar isomer:

Example 3682-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((S)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-((R)-isopropylsulfinyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid;

Less polar isomer (t_(R)=21.45 min).

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.23-7.27 (m, 2H), 7.10 (td, J=7.9,15.7 Hz, 4H), 6.96 (s, 1H), 6.81 (d, J=7.4 Hz, 1H), 4.75 (s, 1H),3.07-3.54 (m, 3H), 2.70-3.01 (m, 3H), 2.58 (d, J=10.4 Hz, 1H), 2.27-2.40(m, 1H), 2.01-2.17 (m, 1H), 1.95 (dd, J=2.6, 13.8 Hz, 1H), 1.55-1.69 (m,1H), 1.46 (s, 3H), 1.23-1.35 (m, 6H), 0.52 (d, J=14.3 Hz, 3H); MassSpectrum (ESI) m/z=538.2 [M−H]⁻, 540.2 [M+H]⁺.

Example 3692-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3S)-2-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium4-methylbenzenesulfonate

To a solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one(2.25 g, 4.89 mmol; Example 151, Step C) in toluene (65 mL) was addedp-toluenesulfonic acid monohydrate (930 mg, 4.89 mmol). After beingheated to reflux using a Dean-Stark trap for 2.5 h, the reaction wasconcentrated under reduced pressure to provide the title compound as apale yellow powder.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3S)-2-(methylsulfonyl)pentan-3-yl)piperidin-2-oneand(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-(methylsulfonyl)pentan-3-yl)piperidin-2-one

The reaction was set in a high pressure reaction vessel. To a solutionof(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium4-methylbenzenesulfonate (0.200 g, 0.325 mmol; Example 370, step A) inacetonitrile (2 ml) was added sodium methanesulfinate (0.166 g, 1.627mmol) at 25° C. Then the reaction was heated to 110° C. for 24 h. Thereaction was quenched with sat. aq. NH₄Cl solution, extracted (2×EtOAc)and washed (2×brine). The combined organic layers were dried (Na₂SO₄)and concentrated under reduced pressure. Purification by chromatographyon silica gel (40 g SiO₂, gradient elution, 20% to 40% EtOAc in hexanes)provided the title compounds as a mixture of two stereoisomers.

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3S)-2-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-(methylsulfonyl)pentan-3-yl)-2-oxopiperidin-3-yl)aceticacid

The title compound was obtained from a mixture of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2S,3S)-2-(methylsulfonyl)pentan-3-yl)piperidin-2-oneand(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((2R,3S)-2-(methylsulfonyl)pentan-3-yl)piperidin-2-one(Example 370, Step B) by a procedure similar to the one described inExample 71, Step F. The crude product was purified by reversed phasepreparatory HPLC (Gemini™ Prep C₁₈ 5 μm column; Phenomenex, Torrance,Calif.; eluent: 40 to 60% acetonitrile, water, 0.1% TFA, gradientelution) to provide the title compound as the first eluting isomer as asingle stereoisomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.46 (t, J=7.5 Hz, 3 H) 1.55 (s, 3H) 1.60 (d, J=7.2 Hz, 3 H) 1.78-1.81 (m, 1 H) 1.84-1.93 (m, 1 H)2.29-2.43 (m, 2 H) 2.72 (d, J=15.5 Hz, 1H) 2.93 (s, 3 H) 2.97-3.09 (m, 2H) 3.14 (m, 1 H) 3.53 (m, 1 H) 5.00 (d, J=10.6 Hz, 1 H) 6.82 (m, 1 H)6.92-6.97 (m, 1 H) 7.07-7.18 (m, 2 H), 7.27 (m, 4 H);

Mass Spectrum (ESI) m/z=540 (M+1).

Example 3702-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-2-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid; first eluting isomer

The title compound was prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium4-methylbenzenesulfonate (Example 369, Step A) by a procedure similar tothe one described in Example 369, replacing sodium methanesulfinate instep B with sodium ethanesulfinate. The crude product was purified byreversed phase preparatory HPLC (Gemini™ Prep C₁₈ 5 mm column;Phenomenex, Torrance, Calif.; eluent: 40 to 60% acetonitrile, water,0.1% TFA, gradient elution) to provide the title compound as the firsteluting isomer as a single stereoisomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.45 (t, J=7.53 Hz, 3 H) 1.41 (t,J=7.53 Hz, 3 H) 1.48-1.62 (m, 6 H) 1.69-1.92 (m, 2 H) 2.29-2.43 (m, 2 H)2.70 (d, J=15.45 Hz, 1 H) 2.92-3.19 (m, 5 H) 3.49-3.56 (m, 1 H) 5.02 (d,J=10.56 Hz, 1H) 6.84 (dt, J=6.99, 1.88 Hz, 1 H) 6.95 (t, J=1.96 Hz, 1 H)7.08-7.19 (m, 3 H) 7.25 (br s, 3 H); Mass Spectrum (ESI) m/z=554 (M+1).

Further elution provided:

Example 3712-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-((2R,3S)-2-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-(ethylsulfonyl)pentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid; second eluting isomer

The title compound was obtained in Example 370 as the second elutingisomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.20 (t, J=7.63 Hz, 3 H) 1.12-1.30(m, 3 H) 1.30-1.45 (m, 6 H) 1.45-1.60 (m, 1 H) 1.71-1.80 (m, 1 H)1.85-1.98 (m, 1 H) 2.40 (t, J=13.79 Hz, 1 H) 2.63 (d, J=15.26 Hz, 1 H)2.86-3.09 (m, 5 H) 4.05-4.19 (m, 1 H) 4.93 (d, J=10.76 Hz, 1 H) 6.78(dt, J=6.90, 1.93 Hz, 1 H) 6.89 (t, J=1.96 Hz, 1 H) 6.95-7.11 (m, 4 H)7.11-7.25 (m, 2 H); Mass Spectrum (ESI) m/z=554 (M+1).

Example 3722-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A. Methyl2-((3R,5R,6S)-1-((S)-1-(benzylthio)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate

To a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(214.4 mg, 0.448 mmol; Example 186, Step A) in toluene (2.0 mL) wasadded benzyl mercaptan (0.106 mL, 0.90 mmol), followed bycyanomethylenetributylphosphorane (0.235 mL, 0.896 mmol; TCI). Thesolution was heated at 100° C. for 3.75 hours, then concentrated invacuo. Purification of the residue by chromatography on silica gel (12 gSiO₂, 0% to 50% EtOAc in hexanes) provided the title compound ascolorless oil.

Step B.(S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonicacid

To a solution of methyl2-((3R,5R,6S)-1-((S)-1-(benzylthio)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(1.31 g, 2.24 mmol; Example 372, Step A) in acetic acid (9.5 ml) andwater (1.0 ml) was added hydrogen peroxide (31.3% solution in water,0.23 ml, 2.35 mmol). The resulting solution was stirred at roomtemperature for 3 hours, then chlorine gas was bubbled into the reactionfor one minute. After stirring at room temperature for one hour, thereaction was concentrated in vacuo, then a few mL of anhydrous benzenewere added and the solvent was removed under reduced pressure on arotary evaporator. This procedure was repeated several times to providethe title compound as a yellow solid. This crude material was useddirectly in the next step without purification.

Step C. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetate

To a solution of(S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonicacid (189.8 mg, 0.35 mmol; Example 372, Step B) in dichloromethane (5.0mL) was added oxalyl chloride (0.061 mL, 0.70 mmol), followed by DMF (2drops). The reaction was stirred at room temperature for 3.5 hours, thenconcentrated in vacuo. The sulfonyl chloride intermediate was dissolvedin dichloromethane (5.0 mL), then treated with 3-oxetanamine (50.0 mg,0.684 mmol; Pharmablock R & D Co. Ltd., Nanjing, China) andN,N-diisopropylethylamine (0.122 mL, 0.699 mmol). After stirring at roomtemperature for 16 hours, the reaction was quenched with methanol (2.0mL), then concentrated in vacuo. Purification of the residue bychromatography on silica gel (4 g SiO₂, 0%-50% EtOAc in hexanes)provided the title compound as a colorless oil.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-yl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)acetate(41.1 mg, 0.069 mmol; Example 372, Step C) in THF (2.0 ml) and MeOH (1.0ml) was added 1 N lithium hydroxide (3.0 ml, 3.0 mmol). The suspensionwas stirred at room temperature for 15 hours, then acidified to pH 4using 1 N HCl, and then concentrated in vacuo. Purification of theresidue by chromatography on silica gel (4 g SiO₂, 5 to 25% gradient ofa 1:6.5 MeOH/acetone mixture in hexanes) provided the title compound.The material was purified further by reversed phase preparatory HPLC(Eclipse Plus C₁₈, 30×250 mm, 5 um column; Agilent, Santa Clara, Calif.)(eluent: 0.1% TFA in acetonitrile/water, gradient 30% to 60% over 25min) to provide the title compound, as a white solid.

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.39 (t, J=7.5 Hz, 3 H) 1.38 (s, 3H) 1.45-1.56 (m, 1 H) 1.91-2.01 (m, 1 H) 2.02-2.08 (m, 1 H) 2.26 (t,J=13.7 Hz, 1 H) 2.59 (d, J=13.7 Hz, 1 H) 2.88-2.99 (m, 2 H) 3.07-3.19(m, 1 H) 3.34-3.41 (m, 2 H) 3.91-4.01 (m, 1 H) 4.55-4.66 (m, 3 H)6.91-6.97 (m, 1H) 7.02 (s, 1H) 7.10-7.19 (m, 3 H) 7.28 (br s, 3 H); MassSpectrum (ESI) m/z=583.2 [M+H]⁺.

Examples 373 and 374 were prepared from(S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-methoxy-2-oxoethyl)-3-methyl-2-oxopiperidin-1-yl)butane-1-sulfonicacid (Example 372, Step B) by procedures similar to the one described inExample 372, replacing 3-oxetanamine in step B with the appropriatereagent.

Example R Reagent used 373

(3-methyloxetan-3-yl) methanamine (Pharmablock R & D Co. Ltd., Nanjing,China) 374

oxetan-3-ylmethanamine (Pharmablock R & D Co. Ltd., Nanjing, China)

Example 3732-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-((3-methyloxetan-3-yl)methyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.42 (t, J=7.58 Hz, 3 H) 1.25 (s, 2H) 1.34 (s, 3 H) 1.39 (s, 3 H) 1.53 (ddd, J=14.24, 7.76, 3.18 Hz, 1 H)1.97-2.08 (m, 2 H) 2.16 (s, 1 H) 2.18 (s, 1 H) 2.29 (t, J=13.69 Hz, 1 H)2.57-2.64 (m, 1 H) 2.95 (d, J=13.45 Hz, 1 H) 3.00-3.06 (m, 1 H) 3.19 (brs, 1 H) 3.35-3.42 (m, 1 H) 4.04 (t, J=12.35 Hz, 1 H) 4.37 (d, J=6.11 Hz,1H) 4.54 (d, J=6.11 Hz, 1H) 4.91 (d, J=10.76 Hz, 1H) 6.96 (d, J=7.34 Hz,1 H) 7.03 (s, 1 H) 7.11-7.20 (m, 3 H) 7.28 (br s, 3 H); Mass Spectrum(ESI) 611.2 [M+H]⁺.

Example 3742-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-(oxetan-3-ylmethyl)sulfamoyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

¹H NMR (500 MHz, methanol-d₄) δ ppm 0.41 (t, J=7.58 Hz, 3 H) 1.38 (s, 3H) 1.46-1.59 (m, 1 H) 2.01-2.08 (m, 2 H) 2.28 (t, J=13.69 Hz, 1 H) 2.60(d, J=13.69 Hz, 1 H) 2.94 (d, J=13.69 Hz, 1 H) 3.03 (d, J=12.47 Hz, 1 H)3.10-3.25 (m, 3 H) 3.34-3.42 (m, 2 H) 3.95-4.07 (m, 1 H) 4.42-4.51 (m, 2H) 4.76-4.82 (m, 2 H) 4.88-4.91 (m, 1H) 6.95 (dt, J=7.03, 1.62 Hz, 1 H)7.00-7.04 (m, 1 H) 7.09-7.18 (m, 3 H) 7.28 (br s, 3 H); Mass Spectrum(ESI) 597.1 [M+H]⁺.

Example 3752-((3R,5R,6S)-1-((S)-2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-1-((S)-2-(benzylthio)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

A mixture of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(1.35 g, 2.94 mmol; Example 252, Step A), benzyl mercaptan (0.691 ml,5.89 mmol) and 2-(tributylphosphoranylidene) in acetonitrile (1.579 ml,5.89 mmol) was heated to 100° C. for 2 h. The reaction mixture wascooled to RT, and extracted with 80 mL of EtOAc. The combined organicswere washed with sat. aq. NH₄Cl solution and brine, dried over Na₂SO₄,filtered and the filtrate was concentrated. The crude product waspurified by chromatography on silica gel eluting with 0 to 50%EtOAc/hexane to give the title compound.

Mass Spectrum (ESI) m/z=564.1 (M+1).

Step B.2-((3R,5R,6S)-1-((S)-2-(N-(tert-Butyl)sulfamoyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of(3S,5R,6S)-3-allyl-1-((S)-2-(benzylthio)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(0.075 g, 0.133 mmol; Example 375, Step A) in 5 mL of a mixture ofMeCN/HOAc/H₂O (40:1.5:1) at 0° C. was added portionwise1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.052 g, 0.266 mmol)(Alfa Aesar, Ward Hill, Mass.). The reaction mixture was stirred at 0°C.-5° C. for 2 h. This solution was added into a mixture oftert-butylamine (97 mg, 140 uL, 5.0 eq.) and DIEA (5.0 eq.) in 2 mL ofDCM at 0° C. The resulting mixture was stirred at room temperature for 3h. The solvents were removed under reduced pressure and residue waspurified by chromatography on silica gel eluting with 30 to 80%EtOAc/hexane to provide the corresponding sulfonamide. This sulfonamidewas converted into the title compound by a procedure similar to the onedescribed in Example 71, Step F. The crude product was purified byreverse phase HPLC (40 to 90% acetonitrile in water, gradient with 0.1%TFA) to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.09 (br s, 1 H), −0.26 (br s, 1H), 0.19-0.50 (m, 2 H), 1.42 (s, 9 H), 1.54 (s, 3 H), 1.88 (d, J=13.30Hz, 2 H), 2.48 (d, J=12.32 Hz, 1 H), 2.76 (d, J=15.26 Hz, 1 H),2.97-3.26 (m, 3 H), 4.14-4.52 (m, 2 H), 4.82 (d, J=10.76 Hz, 1 H), 6.86(d, J=5.87 Hz, 1 H), 6.97 (s, 1H), 7.06-7.22 (m, 3 H), 7.29 (br s, 3 H).Mass Spectrum (ESI) m/z=595.2 (M+1).

Examples 376 to 382 were prepared from(3S,5R,6S)-3-allyl-1-((S)-2-(benzylthio)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(Example 375, Step A) by procedures similar to the one described inExample 375, replacing tert-butylamine in step B with the appropriatereagent.

Example R Reagent used 376

methylamine 377

dimethylamine 378

isopropylamine 379

morpholine 380

piperidine 381

pyrrolidine 382

azetidine

Example 3762-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-methylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.13-−0.88 (m, 1 H), −0.23 (br s,1 H), 0.23-0.50 (m, 2 H), 1.51 (s, 3 H), 1.70-1.89 (m, 1 H), 2.10-2.16(m, 1 H), 2.21-2.32 (m, 1H), 2.40-2.51 (m, 1 H), 2.78 (d, J=15.26 Hz, 1H), 2.84 (d, J=3.52 Hz, 3 H), 2.93-3.06 (m, 1 H), 3.07-3.23 (m, 2 H),3.52-3.67 (m, 1 H), 4.82 (d, J=10.37 Hz, 1 H), 6.83 (d, J=7.24 Hz, 1 H),6.96 (s, 1 H), 7.12-7.15 (m, 3 H), 7.19-7.27 (m, 3 H). Mass Spectrum(ESI) m/z=553.0. (M+1).

Example 3772-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N,N-dimethylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.07 (br s, 1 H), −0.28 (br s, 1H), 0.18-0.44 (m, 2 H), 1.53 (s, 3 H), 1.87 (dd, J=13.79, 2.84 Hz, 2 H),2.50 (t, J=13.79 Hz, 1 H), 2.60 (br s, 1 H), 2.73-2.84 (m, 2 H), 2.90(s, 6 H), 3.07-3.19 (m, 2 H), 4.19 (t, J=12.42 Hz, 1 H), 4.83 (d,J=10.56 Hz, 1 H), 6.83-6.89 (m, 1 H), 6.95 (s, 1 H), 7.07-7.16 (m, 3 H),7.27 (br s, 3 H). Mass Spectrum (ESI) m/z=567.0 (M+1).

Example 3782-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(N-isopropylsulfamoyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.08 (br s, 1 H), −0.27 (br s, 1H), 0.19-0.49 (m, 2 H), 1.22-1.33 (m, 6 H), 1.50 (s, 3 H), 1.67-1.99 (m,2 H), 2.44 (br s, 1 H), 2.58 (br s, 1 H), 2.77 (d, J=14.87 Hz, 1 H),2.98 (d, J=10.76 Hz, 1 H), 3.02-3.25 (m, 2 H), 3.64 (d, J=6.26 Hz, 1 H),4.10-4.46 (m, 1 H), 4.81 (d, J=10.56 Hz, 1 H), 6.84 (d, J=6.46 Hz, 1 H),6.95 (s, 1 H), 7.06-7.16 (m, 3 H), 7.27 (br s, 3 H). Mass Spectrum (ESI)m/z=581.2 (M+1).

Example 3792-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(morpholinosulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.06 (br s, 1 H), −0.29 (br s, 1H), 0.19-0.44 (m, 2 H), 1.50 (s, 3 H), 1.79-1.94 (m, 2 H), 2.47 (t,J=13.89 Hz, 1 H), 2.60 (br s, 1 H), 2.79 (d, J=15.06 Hz, 2 H), 3.08 (d,J=15.06 Hz, 1 H), 3.11-3.20 (m, 1 H), 3.24-3.30 (m, 4 H), 3.77-3.83 (m,4 H), 4.22 (t, J=12.52 Hz, 1 H), 4.82 (d, J=10.76 Hz, 1 H), 6.86 (d,J=7.04 Hz, 1 H), 6.95 (s, 1 H), 7.06-7.16 (m, 3 H), 7.21-7.33 (m, 3 H).Mass Spectrum (ESI) m/z=609.2 (M+1).

Example 3802-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(piperidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.09 (br s, 1 H), −0.30 (br s, 1H), 0.20-0.43 (m, 2 H), 1.53 (s, 3 H), 1.56-1.62 (m, 2 H), 1.63-1.96 (m,5 H), 2.00-2.13 (m, 1 H), 2.52 (t, J=13.79 Hz, 1 H), 2.60 (br s, 1 H),2.71-2.81 (m, 2 H), 3.07-3.20 (m, 2 H), 3.24 (t, J=5.28 Hz, 4 H), 4.13(d, J=13.11 Hz, 1 H), 4.85 (d, J=10.76 Hz, 1 H), 6.86 (d, J=7.04 Hz, 1H), 6.94 (s, 1 H), 7.07-7.18 (m, 3 H), 7.23-7.38 (m, 3 H). Mass Spectrum(ESI) m/z=607.2 (M+1).

Example 3812-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(pyrrolidin-1-ylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.08 (br s, 1 H), −0.28 (br s, 1H), 0.17-0.42 (m, 2H), 1.52 (s, 3H), 1.81 (br s, 1 H), 1.88 (dd,J=13.79, 2.84 Hz, 1 H), 1.94-2.01 (m, 4 H), 2.50 (t, J=13.79 Hz, 1 H),2.62 (br s, 1 H), 2.78 (d, J=15.06 Hz, 1 H), 2.86 (d, J=12.13 Hz, 1 H),3.05-3.20 (m, 2 H), 3.28-3.45 (m, 4 H), 4.24 (br s, 1 H), 4.84 (d,J=10.56 Hz, 1 H), 6.89 (d, J=6.65 Hz, 1 H), 6.98 (s, 1 H), 7.07-7.19 (m,3 H), 7.21-7.37 (m, 3 H). Mass Spectrum (ESI) m/z=593.0 (M+1).

Example 3822-((3R,5R,6S)-1-((S)-2-(Azetidin-1-ylsulfonyl)-1-cyclopropylethyl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −1.07 (br s, 1 H), −0.28 (br s, 1H), 0.18-0.44 (m, 2 H), 1.51 (s, 3 H), 1.80 (br s, 1 H), 1.90 (dd,J=13.79, 2.84 Hz, 1 H), 2.31 (quin, J=7.68 Hz, 2 H), 2.45 (t, J=13.79Hz, 1 H), 2.60 (br s, 1 H), 2.74-2.82 (m, 1 H), 2.94 (d, J=13.69 Hz, 1H), 3.07 (d, J=14.87 Hz, 1 H), 3.16 (ddd, J=13.74, 10.71, 2.74 Hz, 1 H),3.94-4.06 (m, 4 H), 4.27 (br s, 1 H), 4.82 (d, J=10.56 Hz, 1 H),6.81-6.88 (m, 1 H), 6.97 (m, 1 H), 7.07-7.17 (m, 3 H), 7.24-7.28 (m, 3H). Mass Spectrum (ESI) m/z=579.0 (M+1).

Example 3832-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((N,N-dimethylsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[(dimethylsulfamoyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperidin-2-one

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 252, Step A) and N,N-dimethylsulfamide (TCI America, Portland,Oreg.) following a procedure similar to the one described in Example202, Step C.

Mass Spectrum (ESI) m/z=561.5 (M+1).

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((N,N-dimethylsulfamoyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[(dimethylsulfamoyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperidin-2-one(Example 383, Step A) following a procedure similar to the one describedin Example 226, Step D.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.34 (br s, 1H), 0.02-0.19 (m,1H), 0.42-0.60 (m, 2H), 1.14 (br s, 1H), 1.40-1.52 (m, 4H), 2.00-2.14(m, 1H), 2.18-2.38 (m, 1H), 2.79 (s, 6H), 2.80-2.83 (m, 1H), 2.90-3.00(m, 1H), 3.00-3.12 (m, 1H), 3.12-3.29 (m, 2H), 3.79 (br s, 1H), 4.89 (d,J=10.2 Hz, 1H), 6.82 (d, J=7.4 Hz, 1H), 6.94-7.02 (m, 1H), 7.03-7.21 (m,4H), 7.24-7.28 (m, 2H); Mass Spectrum (ESI) m/z=582.0 (M+1).

Example 3842-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[(dimethylsulfamoyl)(methyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperidin-2-one

The title compound was prepared from(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[(dimethylsulfamoyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperidin-2-one(Example 383, Step A) following a procedure similar to the one describedin Example 264.

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-((N,N-dimethylsulfamoyl)(methyl)amino)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-[(1S)-1-cyclopropyl-2-[(dimethylsulfamoyl)(methyl)amino]ethyl]-3-methyl-3-(prop-2-en-1-yl)piperidin-2-one(example 384, Step A) following a procedure similar to the one describedin Example 226, Step D.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.76 (br s, 1H), −0.34 (br s, 1H),0.32 (br s, 1H), 0.42 (br s, 1H), 1.43-1.61 (m, 3H), 1.62-1.84 (m, 1H),1.94 (d, J=13.3 Hz, 2H), 2.21 (d, J=12.9 Hz, 1H), 2.44 (br s, 1H),2.73-2.90 (m, 9H), 3.03-3.21 (m, 3H), 4.65 (br s, 6H), 4.81 (d, J=10.2Hz, 2H), 6.83-6.96 (m, 2H), 7.00 (s, 2H), 7.08-7.18 (m, 3H), 7.25 (br s,1H); Mass Spectrum (ESI) m/z=596.0 (M+1).

Examples 385 to 389 were prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-hydroxyethyl)-3-methylpiperidin-2-one(Example 252, step A) following procedures similar to the one describedin Example 202, Step C and D, replacing N-methylcyclopropanesulfonamidein step B with the appropriate reagent.

Example R Reagent used 385

1-methylhydantoin (Sigma-Aldrich, St. Louis, MO) 386

1,5,5-trimethylimidazolidine-2,4-dione (Sigma-Aldrich, St. Louis, MO))387

5,5-dimethylimidazolidine-2,4-dione (Sigma-Aldrich, St. Louis, MO) 388

bentazon (Chem Service, West Chester, PA) 389

1H-benzo[d]imidazol-2(3H)-one (Sigma-Aldrich, St. Louis, MO)

Example 3852-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(3-methyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxoppiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.24 (br s, 1H), 0.58 (br s, 2H),1.12-1.36 (m, 1H), 1.36-1.55 (m, 3H), 1.99-2.11 (m, 1H), 2.11-2.26 (m,1H), 2.71 (d, J=15.1 Hz, 1H), 3.01-3.08 (m, 4H), 3.08-3.23 (m, 2H), 3.53(br s, 1H), 3.78-4.01 (m, 3H), 4.63 (br s, 1H), 5.58 (br s, 1H), 6.68(d, J=7.6 Hz, 1H), 6.92-7.02 (m, 1H), 7.06-7.22 (m, 3H), (7.24-7.32 (m,3H); Mass Spectrum (ESI) m/z=572.0 (M+1).

Example 3862-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxoppiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.23 (br s, 1H), 0.56 (br s, 2H),1.32-1.55 (m, 10H), 2.02 (dd, J=13.9, 2.7 Hz, 1H), 2.15-2.32 (m, 1H),2.72 (d, J=15.1 Hz, 1H), 2.84-2.96 (m, 4H), 3.04-3.25 (m, 3H), 3.55 (brs, 1H), 3.87-4.10 (br s, 1H), 4.87 (br s, 1H), 6.66 (d, J=7.0 Hz, 1H),6.99 (s, 1H), 7.08 (t, J=7.8 Hz, 2H), 7.17 (d, J=8.6 Hz, 2H), 7.28 7.32(m, 2H); Mass Spectrum (ESI) m/z=600.0 (M+1).

Example 3872-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(4,4-dimethyl-2,5-dioxoimidazolidin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.18 (br s, 1H), 0.56 (br s, 2H),1.37-1.52 (m, 11H), 2.05 (dd, J=13.89, 2.93 Hz, 1H), 2.20 (t, J=13.40Hz, 1H), 2.74 (d, J=14.9 Hz, 1H), 3.05 (d, J=14.9 Hz, 1H), 3.18 (ddd,J=12.81 9.9, 3.1 Hz, 1H), 3.53 (br s, 1H), 3.99 (br s, 1H), 4.67 (br s,1H), 5.31 (s, 1H), 5.44-5.73 (m, 5H), 6.27 (br s, 1H), 6.68 (d, J=7.4Hz, 1H), 6.99 (s, 1H), 7.05-7.13 (m, 2H), 7.13-7.21 (m, 2H), 7.22 (br s,1H);

Mass Spectrum (ESI) m/z=586.0 (M+1).

Example 3882-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(3-isopropyl-2,2-dioxido-4-oxo-3,4-dihydro-1H-benzo[c][1,2,6]thiadiazin-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.11 (br s, 1H), 0.45 (br s, 2H),1.22-1.34 (m, 1H), 1.43-1.66 (m, 9H), 1.95-2.14 (m, 1H), 2.21 (t,J=13.60 Hz, 1H), 2.83 (d, J=14.7 Hz, 1H), 3.07 (d, J=14.5 Hz, 1H),3.14-3.28 (m, 1H), 3.51 (s, 3H), 3.69 (br s, 1H), 4.79 (br s, 1H),4.95-5.12 (m, 1H), 6.78 (d, J=7.43 Hz, 1H), 6.93 (br s, 1H), 7.01 (br s,1H), 7.04-7.20 (m, 3H), 7.28-7.31 (m, 3H), 7.39 (t, J=7.4 Hz, 1H),7.59-7.70 (m, 1H), 8.19 (d, J=8.0 Hz, 1H); Mass Spectrum (ESI) m/z=698.0(M+1).

Example 3892-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.29-−0.06 (m, 1H), 0.41 (br s,2H), 1.32-1.43 (m, 3H), 1.43-1.60 (m, 2H), 1.64-1.94 (m, 3H), 2.75 (d,J=14.1 Hz, 1H), 2.97 (d, J=14.1 Hz, 1H), 3.11 (br s, 1H), 3.51-3.72 (m,1H), 3.74 (m, 1H), 4.34 (s, 1H), 6.45 (br s, 1H), 6.63 (br s, 1H), 6.75(br s, 1H), 7.01 (d, J=6.5 Hz, 2H), 7.11 (d, J=7.6 Hz, 2H), 7.15-7.27(m, 4H), 9.55 (br s, 1H); Mass Spectrum (ESI) m/z=592.0 (M+1).

Example 3902-((3R,5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)piperidin-2-one

The title compound was prepared using 2-(3-chloro-4-fluorophenyl)aceticacid according to the procedures described in Example 1, Steps A-E. Theindividual enantiomers were separated by chiral HPLC (flowrate: 400mL/min on a Varian SD-2 prep HPLC system (Wakefield, R.I.) and a MODCOLspring load column from Grace (Hesperia, Calif.) with an inner diameterof 10 cm and packed to a length of approximately 35 cm with 2.0 kg ofChiralcel® OD CSP (Chiral Technologies, Inc., West Chester, Pa., USA)using 25% isopropyl alcohol/methanol as the eluent) to give the titlecompound as an off-white solid. [α]_(D)=+152° (T=23° C., c=1.0, CHCl₃).

Step B.(4R,5S)-5-Amino-4-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pentanoicacid hydrochloride

A suspension of(5R,6S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)piperidin-2-one(5.00 g, 14.78 mmol; Example 390, step A) in 5 M HCl (15 mL) was heatedto reflux for seven hours. The reaction mixture was cooled to rt anddiluted with toluene. The solvent was removed in vacuo and any remainingwater was removed by azeotropic distillation with toluene four times toprovide a white solid (5.81 g).

Step C.(5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropylpiperidin-2-one

Sodium triacetoxyborohydride (1.796 g, 8.48 mmol) was added to asolution of(4R,5S)-5-amino-4-(3-chloro-4-fluorophenyl)-5-(4-chlorophenyl)pentanoicacid hydrochloride (2.56 g, 6.52 mmol; Example 390, Step B) and acetone(0.491 mL, 6.68 mmol) in anhydrous DMF (6.52 mL) at rt. The reactionmixture was stirred at rt for 16 hours. Dichloroethane (25 mL) was addedfollowed by 3 Å molecular sieves. The reaction mixture was heated to 70°C. for 22 hours, filtered and concentrated in vacuo. Purification byflash chromatography on silica gel using a 220 g column and eluting with30 to 100% EtOAc/hexanes provided the desired product as a white solid.

Step D.(3S,5R,6S)-3-Allyl-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one

A solution of(5R,6S)-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropylpiperidin-2-one(0.50 g, 1.32 mmol; Example 390, Step C) in anhydrous THF (3 mL) wasdegassed by bubbling argon through the solution for 15 minutes. LHMDS (1M in THF that was degassed by bubbling argon through the solution for 15minutes) (1.64 mL, 1.64 mmol) was added to the lactam solution at −15°C. dropwise while keeping the temperature below −8° C. After 15 minutesat −15° C. iodomethane (0.085 mL, 1.354 mmol) was added. Thirty fiveminutes later freshly prepared LDA (3.29 mmol) in THF (1 mL) was addedto the reaction mixture. After 30 minutes the reaction mixture wascooled to −78° C. and allyl bromide (0.398 mL, 4.60 mmol) was addedslowly while keeping the temperature at or below −68° C. The reactionmixture was allowed to warm as the cold bath warmed. After 16 hours thereaction mixture temperature was 18° C. The reaction was quenched withMeOH (0.5 mL), washed with 10 mL of 50% brine/water, brine, dried(Na₂SO₄), decanted and concentrated in vacuo to provide a yellow oil.Purification by flash chromatography on silica gel (eluent: 5-15%EtOAc/hexanes, gradient elution) provided the title compound.

Step E.2-((3R,5R,6S)-5-(3-Chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid

A solution of potassium permanganate (0.341 g, 2.155 mmol) in water (2mL) was added to a solution of(3S,5R,6S)-3-allyl-5-(3-chloro-4-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one(0.312 g, 0.718 mmol; Example 390, step D) and tetrabutylammoniumchloride hydrate (0.021 g, 0.072 mmol) in DCM (2 mL) at 0° C. After 5minutes the reaction mixture was removed from the ice bath and stirredat rt. After 2 hours at rt the reaction mixture was diluted with aq.sodium bisulfite. This solution was filtered and then extracted with DCMthree times. The combined organics were pooled, washed with 50 mL of 10%sodium bisulfite, brine, dried (MgSO₄), filtered and concentrated invacuo to provide a yellow oil. Purification by flash chromatography onsilica gel using a 24 g column and eluting with 0 to 50% IPA/hexanesprovided fractions containing the desired product and an impurity. Uponstanding over night the desired product crystallized as colorless prismsand were collected by vacuum filtration to provide the title compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 1.25 (d, J=6.8 Hz, 3 H), 1.26 (d,J=6.8 Hz, 3 H), 1.40 (s, 3 H), 2.00 (dd, J=3.4 and 13.9 Hz, 1 H), 2.09(dd, J=11.9 and 13.7 Hz, 1 H), 2.67 (d, J=15.4 Hz, 1 H), 3.02 (dt, J=3.2and 9.3 Hz, 1 H), 3.03 (d, J=15.4 Hz, 1 H), 3.41 (m, 1 H), 4.41 (d,J=9.0 Hz, 1 H), 6.70-6.73 (m, 1 H), 6.95-6.99 (m, 3 H), 7.06 (dd, J=2.5and 6.9 Hz, 1 H), 7.28 (d, J=9.5 Hz, 2 H); Mass Spectrum (ESI) m/z=452.2[M+H]⁺.

Example 3912-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)piperidin-2-one

The title compound was prepared using 2-(3-chloro-5-fluorophenyl)aceticacid according to the procedures described in Example 1, Steps A-E. Theindividual enantiomers were separated by chiral HPLC (150×50 mmChiralpak® AD-H column (Chiral Technologies, Inc., West Chester, Pa.,USA) with 50 g/min methanol+(20 mM NH₃)+130 g/min CO₂ on Thar 350 SFC(Thar Technologies, Inc., Pittsburgh, Pa.)). [α]_(D)=+114° (T=23° C.,c=4.0, CHCl₃).

Step B.(4R,5S)-5-Amino-4-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)pentanoicacid hydrochloride

The title compound was prepared from(5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 391, Step A) using the procedure described in Example 390, StepB.

Step C.(5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropylpiperidin-2-one

The title compound was prepared from(4R,5S)-5-amino-4-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)pentanoicacid hydrochloride (Example 391, step B) using the procedure describedin Example 390, Step C.

Step D.(3S,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-oneand(3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylppiperidin-2-one

A solution of(5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropylpiperidin-2-one(0.400 g, 1.052 mmol; Example 391, Step C) was dissolved in benzene andthe solvent removed under a vacuum three times. The resulting oil wasdissolved in anhydrous 2-methylTHF (2 mL) and was degassed by bubblingargon through the solution for 15 minutes while cooling to −15° C. LHMDS(1.0 M in THF) (1.315 ml, 1.315 mmol) was added and the solution turnedyellow. After 10 minutes, iodomethane (0.069 ml, 1.104 mmol) was addeddropwise while keeping the temperature below −10° C. Forty minutes laterthe reaction mixture was quenched with sat. aq. NH₄Cl and warmed to rt.The layers were separated and the aqueous layer was extracted with EtOActwice. The organics were pooled, washed with brine, dried (Na₂SO₄),decanted and concentrated in vacuo to provide an orange oil.Purification by flash chromatography on silica gel using a 24 g columnand eluting with 10 to 30% EtOAc/hexanes provided a 96:4 mixture of(3S,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-oneand(3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-oneas a colorless syrup.

Step E.(3S,5R,6S)-3-Allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-oneand(3R,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one

A solution of(3S,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-oneand(3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one(0.320 g, 0.812 mmol; Example 391, Step D) in anhydrous 2-methylTHF (1.5mL) was degassed by bubbling argon through the solution for 15 minutesand then cooled to −15° C. Freshly prepared LDA (1.22 mmol) in2-methyl-THF (1.5 mL) was added slowly while keeping the temperature ator below −14° C. After 30 minutes at −15° C. the reaction mixture wascooled to −74° C. and allyl bromide (0.176 ml, 2.029 mmol) was addedslowly while keeping the temperature below −70° C. After 2 hoursadditional allyl bromide (0.176 ml, 2.029 mmol) was added and thereaction mixture was allowed to warm to rt. The reaction was quenchedwith sat. aq. NH₄Cl and the layers were separated. The aqueous layer wasextracted with EtOAc twice and the organics were pooled, washed withbrine, dried (Na₂SO₄), decanted and concentrated under a vacuum toprovide a pale yellow oil. Purification by flash chromatography onsilica gel using a 24 g column and eluting with 0 to 50% acetone/hexanesprovided a colorless oil as a 3.3:1 mixture of(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-oneand(3R,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one.

Step F.2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid

Ruthenium(III) chloride hydrate (2.19 mg, 9.72 μmol) was added to asolution of(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-oneand(3R,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methylpiperidin-2-one(0.192 g, 0.442 mmol; Example 391, Step E) and NaIO₄ (97 mg) in EtOAc (1mL), ACN (1 mL) and water (2 mL) at rt. After 3 minutes NaIO₄ (97 mg)was added. The remaining two portions of NaIO₄ (97 mg each) were addedafter three and six minutes respectively. After 30 minutes the reactionmixture was filtered and the layers were separated. The aqueous layerwas extracted with EtOAc twice and the organics were pooled, washed with10% aq. NaHSO₃, brine, dried (Na₂SO₄), decanted and concentrated invacuo to provide a tan oil. Purification by flash chromatography onsilica gel using a 24 g column and eluting with 5 to 30% (15%MeOH/acetone)/hexanes provided a 3.3:1 mixture of2-((3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid and2-((3S,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid (170 mg, 85%). The individual isomers were separated by chiral HPLC(2×(250 mm×30 mm) Chiralpak® AD-H column (Chiral Technologies, Inc.,West Chester, Pa., USA) with 20 g/min methanol+(20 mM NH₃)+80 g/min CO₂on Thar 350 SFC (Thar Technologies, Inc., Pittsburgh, Pa.)) to providethe title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.26 (d, J=6.9 Hz, 3 H), 1.27 (d,J=6.7 Hz, 3 H), 1.38 (s, 3 H), 1.99-2.11 (m, 2 H), 2.65 (d, J=15.7 Hz, 1H), 3.02 (d, J=15.7 Hz, 1 H), 3.30 (dt, J=2.2 and 8.8 Hz, 1 H), 3.46 (m,1 H), 4.48 (d, J=8.8 Hz, 1 H), 6.57 (dt, J=1.8 and 9.2 Hz, 1 H), 6.79(s, 1 H), 6.97 (dt, J=2.2 and 8.4 Hz, 1 H), 6.99 (d, J=8.4 Hz, 2 H),7.30 (d, J=8.6 Hz, 2 H); Mass Spectrum (ESI) m/z=452.2 [M+H]⁺.

Example 3922-((3S,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-isopropyl-3-methyl-2-oxopiperidin-3-yl)aceticacid

Further elution from the HPLC column in Example 391, Step F provided thetitle compound (14.8 mg). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.22 (d,J=6.9 Hz, 3 H), 1.27 (d, J=7.0 Hz, 3 H), 1.58 (s, 3 H), 1.72 (dd, J=3.1and 13.3 Hz, 1 H), 2.32 (t, J=13.5 Hz, 1 H), 2.65-2.75 (m, 2 H), 3.13(dt, J=2.9 and 10.6 Hz, 1 H), 3.26 (m, 1 H), 4.33 (d, J=10.4 Hz, 1 H),6.53 (d, J=9.0 Hz, 1 H), 6.74 (s, 1 H), 6.91-6.97 (m, 3 H), 7.27 (d,J=8.6 Hz, 2 H); Mass Spectrum (ESI) m/z=452.2 [M+H]⁺.

Example 3932-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one

The title compound was prepared as described in Example 185, Step Ereplacing 2-(3-chlorophenyl aceytic acid with2-(3-chloro-5-fluorophenyl)acetic acid in Example 1, Step A.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

To a solution of(3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(2.15 g, 3.06 mmol; Example 393, Step A) in THF (30.6 ml) at rt wasadded TBAF (1.0 M in THF) (6.12 ml, 6.12 mmol). The light yellow mixturewas stirred at rt overnight. The mixture was diluted with water andEtOAc. The organic layer was washed with brine, dried over Na₂SO₄,filtered and the filtrate was concentrated. The residue was purified byflash chromatography on silica gel (40 g column; eluent: 0 to 50% EtOAcin hexanes) to give the title compound.

Step C.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)ethanesulfonamide

(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(100 mg, 0.215 mmol; Example 393, Step B) and ethanesulfonamide (70.5mg, 0.646 mmol) were coupled by the procedure as described in Example202, Step C to form the title compound, isolated after silica gelchromatography (4 g column; eluent 0 to 50% EtOAC/hexanes) as anoff-white solid.

Step D.2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butyl)ethanesulfonamide(Example 393, Step C, 120 mg, 0.216 mmol) in EtOAc:MeCN:water (1.450 mL)(2/2/3) at rt was added sodium periodate (185 mg, 0.864 mmol) slowly.Then ruthenium chloride hydrate (1.071 mg, 4.75 μmol) was added. Themixture was stirred vigourously at rt for 2 h. Then the mixture wasfiltered and the solid was washed with EtOAc. The filtrate was extractedwith EtOAc 2×. The combined organic layers were dried over Na₂SO₄,filtered and the filtrate was concentrated under reduced pressure. Theresidue was purified by reverse phase preparatory HPLC (column: Gemini™Prep C₁₈ 5 um column; Phenomenex, Torrance, Calif.; eluent: 0 to 100%MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.53 (t, J=7.6 Hz, 3 H) 1.40 (t,J=7.3 Hz, 3 H) 1.46-1.56 (m, 4 H) 1.80-1.94 (m, 1 H) 1.96-2.00 (m, 2 H)2.36 (t, J=13.9 Hz, 1 H) 2.77 (d, J=14.9 Hz, 1 H) 2.97 (d, J=14.9 Hz, 1H) 3.02-3.21 (m, 5 H) 4.61 (br s, 1 H) 4.81 (d, J=10.6 Hz, 1 H)6.62-6.69 (m, 1 H) 6.79 (t, J=1.8 Hz, 1 H) 6.90 (dt, J=8.3, 2.1 Hz, 1 H)7.07 (br s, 2 H) 7.24-7.30 (m, 2 H); Mass Spectrum (ESI) m/z=573 (M+1).

Example 3942-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(N-methylethylsulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of2-((3R,5R,6S)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 393, Step D, 26.6 mg, 0.046 mmol) in DMF (464 μl) at rtwas added a dispersion of 60% sodium hydride in mineral oil (5.57 mg,0.139 mmol). The grey slurry was stirred at rt for 30 min theniodomethane (5.80 μl, 0.093 mmol) was added. The mixture was stirred atrt for 1 h. The mixture was quenched with 1 M HCl and diluted withEtOAc. The aqueous layer was extracted with EtOAc 2×. The organic layerwas dried over Na₂SO₄, filtered and the filtrate was concentrated. Theresidue was purified by reverse phase preparatory HPLC (column: Gemini™Prep C₁₈ 10 um column; Phenomenex, Torrance, Calif.; eluent: 0 to 100%MeCN+0.1% TFA in water+0.1% TFA, over 20 minutes) to give the titlecompound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.50 (t, J=7.5 Hz, 3 H) 1.38 (t,J=7.4 Hz, 3 H) 1.52 (s, 3 H) 1.57-1.63 (m, 1 H) 1.85-2.00 (m, 2 H) 2.46(t, J=13.9 Hz, 1 H) 2.66-2.89 (m, 6 H) 2.94-3.16 (m, 4 H) 4.31 (dd,J=13.7, 10.8 Hz, 1 H) 4.81 (d, J=10.8 Hz, 1 H) 6.59 (br s, 1 H) 6.69(dt, J=9.1, 2.1 Hz, 1 H) 6.80 (t, J=1.8 Hz, 1 H) 6.91 (dt, J=8.3, 2.0Hz, 1 H) 7.01 (br s, 1 H) 7.29 (br s, 2 H); Mass Spectrum (ESI) m/z=587(M+1).

Example 3952-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5S,6R,8S)-8-Allyl-6-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 393, Step B) by a procedure similar to the one described inExample 344, Step A.

Step B.(3S,5R,6S)-3-Allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)piperidin-2-one

To a solution of(3S,5S,6R,8S)-8-allyl-6-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (Example 395, step A, 100 mg, 0.184 mmol) in MeCN (1.8mL) was added methanesulfinic acid, sodium salt (56.5 mg, 0.553 mmol).The mixture was heated to 114° C. After heating for 24 hours, themixture was cooled to room temperature and stirred for 2 days. Themixture was partitioned between EtOAc and aq. NH₄Cl. The organic layerwas washed with brine, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (eluent: 20 to 60% EtOAc/hexanes, gradient elution) to afford thetitle compound.

Step C.2-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

To a solution of(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-(methylsulfonyl)butan-2-yl)piperidin-2-one(Example 395, Step B, 58 mg, 0.110 mmol) in acetonitrile (1.0 mL), EtOAc(1.0 mL), and water (1.5 mL) was added ruthenium(III) chloride hydrate(0.55 mg, 2.42 μmol) and sodium periodate (144 mg, 0.672 mmol). After 2hours, the mixture was partitioned between water and EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, filtered and thefiltrate was concentrated. The residue was purified by preparative thinlayer chromatography on silica gel (eluent: 10% MeOH/DCM) to provide thetitle compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.43 (t, J=7.5 Hz, 3 H) 1.48 (s, 3H) 1.64 (br s, 1 H) 1.91 (dd, J=13.7, 2.4 Hz, 1 H) 2.06-2.22 (m, 1 H)2.33 (t, J=13.8 Hz, 1 H) 2.76 (d, J=15.1 Hz, 1 H) 2.90 (d, J=12.1 Hz, 1H) 2.94-3.03 (m, 4 H) 3.13 (t, J=11 Hz, 1H) 3.33 (t, J=9.7 Hz, 1 H) 4.22(t, J=12.3 Hz, 1 H) 4.88 (d, J=10.8 Hz, 1 H) 6.61 (d, J=9.2 Hz, 1 H)6.75 (s, 1 H) 6.89 (dt, J=8.3, 1.9 Hz, 1 H) 7.12 (br s, 2 H) 7.21-7.35(m, 2 H). Mass Spectrum (ESI) m/z=544.0 (M+1).

Examples 396 to 398 were prepared from(3S,5S,6R,8S)-8-allyl-6-(3-chloro-5-fluorophenyl)-5-(4-chlorophenyl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate (Example 395, Step A) by a procedure similar to thosedescribed in either Example 339 or Example 395, using an equivalentamount of the appropriate reagent in Step B. Example 399 was preparedfrom(3S,5R,6S)-3-allyl-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 393, step B) by a procedure similar to the one described inExample 300, using an equivalent amount of the appropriate thiol in StepA.

Example R Method Reagent used 396 Ethyl Example 395 ethanesulfinic acid,sodium salt 397

Example 395 cyclopropanesulfinic acid, sodium salt 398

Example 339 2-methylpropanethiolate, prepared in situ from2-methylpropane-2-thiol and sodium hydride 399

Example 300 2-propanethiol

Example 3962-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.42 (t, J=7.5 Hz, 3 H) 1.45 (t,J=7.5 Hz, 3 H) 1.49 (s, 3 H) 1.65 (br s, 1 H) 1.90 (dd, J=13.7, 2.4 Hz,1 H) 2.06-2.21 (m, 1 H) 2.35 (t, J=13.8 Hz, 1 H) 2.73-2.82 (m, 2 H) 2.98(d, J=15.1 Hz, 1 H) 3.01-3.08 (m, 2 H) 3.13 (t, J=11.0 Hz, 1 H) 3.34 (t,J=10.2 Hz, 1 H) 4.13 (t, J=12.1 Hz, 1 H) 4.92 (d, J=10.8 Hz, 1 H) 6.62(d, J=9.2 Hz, 1 H) 6.75 (s, 1 H) 6.89 (dt, J=8.4, 2.0 Hz, 1 H) 7.12 (brs, 2 H) 7.21-7.34 (m, 2 H). Mass Spectrum (ESI) m/z=558.0 (M+1).

Example 3972-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.43 (t, J=7.6 Hz, 3 H) 1.05-1.15(m, 2 H) 1.25-1.33 (m, 2 H) 1.38-1.54 (m, 4 H) 1.90 (dd, J=13.8, 2.8 Hz,1 H) 2.07-2.21 (m, 1 H) 2.34 (t, J=13.8 Hz, 1 H) 2.42 (tt, J=8.0, 4.8Hz, 1 H) 2.76 (d, J=15.1 Hz, 1 H) 2.88-3.01 (m, 2 H) 3.13 (ddd, J=13.4,10.8, 2.5 Hz, 1 H) 3.31 (t, J=10.4 Hz, 1 H) 4.20 (dd, J=13.5, 11.2 Hz, 1H) 4.90 (d, J=10.8 Hz, 1 H) 6.61 (dt, J=9.0, 2.0 Hz, 1 H) 6.74 (s, 1 H)6.88 (dt, J=8.4, 2.1 Hz, 1 H) 7.11 (br s, 2 H) 7.21-7.34 (m, 2 H). MassSpectrum (ESI) m/z=570.0 (M+1).

Example 3982-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-5-(3-chloro-5-fluorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The crude product was purified by SFC 20 mL/min; 30×250 mm Chiralpak® ICcolumn (Chiral Technologies, Inc., West Chester, Pa., USA) usingmethanol (20 mM NH₃)/CO₂ as the eluent on Thor SFC (Thor Technologies,Inc. Pittsburgh, Pa.) to provide the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 (t, J=7.5 Hz, 3 H) 1.38-1.68(m, 13 H) 1.88 (dd, J=13.7, 2.5 Hz, 1 H) 2.06-2.26 (m, 1 H) 2.38 (t,J=13.8 Hz, 1 H) 2.73 (d, J=15.5 Hz, 1 H) 2.80 (d, J=13.5 Hz, 1 H) 3.01(d, J=15.3 Hz, 1 H) 3.11 (t, J=11.8 Hz, 1 H) 3.33 (t, J=10.4 Hz, 1 H)4.03 (dd, J=13.0, 11.3 Hz, 1 H) 4.97 (d, J=10.8 Hz, 1 H) 6.63 (d, J=9.2Hz, 1 H) 6.75 (s, 1 H) 6.89 (d, J=8.4 Hz, 1 H) 7.14 (br s, 2 H)7.25-7.36 (m, 2 H). Mass Spectrum (ESI) m/z=586.0 (M+1).

Example 3992-((3R,5R,6S)-5-(3-Chloro-5-fluorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

The crude product was purified by preparative thin layer chromatographyon silica gel (eluent: 10% MeOH/DCM) followed by purification by reversephase preparatory HPLC (column: Gemini™ Prep C₁₈ 10 um column;Phenomenex, Torrance, Calif.; eluent: 0 to 100% MeCN+0.1% TFA inwater+0.1% TFA, over 20 minutes) to give the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.41 (t, J=7.5 Hz, 3 H) 1.34-1.55(m, 10 H) 1.88 (dd, J=13.8, 2.6 Hz, 1 H) 2.07-2.24 (m, 1 H) 2.38 (t,J=13.8 Hz, 1 H) 2.68-2.81 (m, 2 H) 3.01 (d, J=15.5 Hz, 1 H) 3.06-3.18(m, 2 H) 3.35 (t, J=10.2 Hz, 1 H) 4.08 (dd, J=13.1, 11.5 Hz, 1 H) 4.95(d, J=10.8 Hz, 1 H) 6.63 (d, J=9.0 Hz, 1 H) 6.75 (s, 1 H) 6.89 (dt,J=8.2, 2.0 Hz, 1 H) 7.14 (br s, 2 H) 7.24-7.37 (m, 2 H). Mass Spectrum(ESI) m/z=572.0 (M+1).

Example 4002-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. 1-(4-Chlorophenyl)-2-(5-chloropyridin-3-yl)ethanone

1-(4-chlorophenyl)ethanone (17.22 ml, 133 mmol) was added to an ice coldsolution of 3-bromo-5-chloropyridine (24.3 g, 126 mmol) and sodium2-methylpropan-2-olate (30.3 g, 316 mmol) in THF (158 ml) under an argonatmosphere. (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine)(0.731 g, 1.263 mmol) and diacetoxypalladium (0.283 g, 1.263 mmol) werethen added and the solution was heated to 70° C. for 1.5 hours. Thesolution was cooled to rt and diluted with ice, 2N HCl (95 mL) followedby EtOAc (300 ml). The layers were partitioned and the aqueous layer waswashed with EtOAc (2×100 ml). The organics were washed with brine, driedover Na₂SO₄, filtered, and concentrated. The residue obtained wasenriched on a silica gel column. The fractions containing the productwere combined and concentrated. To the residue obtained was added 130 mlof Et₂O and the suspension was heated to a reflux in a water bath. Thesuspension was then cooled in an ice bath. The solids were collected byfiltration to provide the title compound.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.53 (1 H, d, J=2.4 Hz), 8.43 (1 H, d,J=1.7 Hz), 8.05-8.11 (2 H, m), 7.85 (1 H, t, J=2.1 Hz), 7.63-7.68 (2 H,m), 4.55 (2 H, s).

Step B. 1-Methyl5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-2-methyl-5-oxopentanoate

The title compound was obtained from1-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)ethanone (Example 400, StepA, 25.3 g, 95 mmol) by a procedure similar to the one described inExample 261, Step A. Racemic product is a 1:1 mixture of diastereomers.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.57 (1 H, d, J=2.0 Hz), 8.54 (1 H, d,J=1.7 Hz), 8.50 (2 H, dd, J=4.4, 2.4 Hz), 8.05-8.09 (4 H, m), 7.90 (2 H,t, J=2.1 Hz), 7.57-7.64 (4 H, m), 4.93-5.04 (2 H, m), 3.54 (3 H, s),3.45 (3 H, s), 2.34-2.42 (1 H, m), 2.24-2.33 (2 H, m), 2.19 (1 H, dt,J=13.7, 6.8 Hz), 2.05-2.13 (1 H, m), 1.88-1.96 (1 H, m), 1.13 (3 H, d,J=7.1 Hz), 1.08 (3 H, d, J=7.1 Hz); Mass Spectrum (ESI) m/z=366.1[M+H]⁺.

Step C. Racemic Mixture of (4R,5R)-methyl5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoateand (4S,5S)-methyl5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoate

1-Methyl5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-2-methyl-5-oxopentanoate(Example 400, Step B, 31 g, 85 mmol) was converted to the titlecompounds by a procedure similar to the one described in Example 261,Step B. Product is a 1:1 mixture of diastereomers at the 2 position.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.43 (2 H, s), 8.13 (2 H, d, J=11.7Hz), 7.59 (2 H, dt, J=6.8, 2.0 Hz), 7.24-7.30 (4 H, m), 7.03-7.10 (4 H,m), 4.88 (1 H, d, J=5.6 Hz), 4.84 (1 H, d, J=5.6 Hz), 3.64 (3 H, s),3.56 (3 H, s), 2.91 (2 H, tt, J=10.7, 5.3 Hz), 2.22-2.29 (1 H, m),2.13-2.22 (4 H, m), 2.00-2.10 (1 H, m), 1.72-1.87 (2 H, m), 1.11 (3 H,d, J=7.1 Hz), 1.09 (3 H, d, J=6.8 Hz); Mass Spectrum (ESI) m/z=368.0[M+H]⁺.

Step D.(4R,5R)-5-(4-Chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoicacid and(4S,5S)-5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoicacid

The racemic mixture of (4R,5R)-methyl5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoateand (4S,5S)-methyl5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoate(Example 400, Step C, 16.5 g, 43.4 mmol) was converted to the titlecompounds by the procedure described in Example 261, Step C. MassSpectrum (ESI) m/z=354.1 [M+H]⁺.

Step E.(5R,6R)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-pyran-2-oneand(5S,6S)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-pyran-2-one

The diastereomeric mixture of(4R,5R)-5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoicacid and(4S,5S)-5-(4-chlorophenyl)-4-(5-chloropyridin-3-yl)-5-hydroxy-2-methylpentanoicacid (Example 400, Step D, 15.39 g, 43.4 mmol) was converted to thetitle compounds by the procedure described in Example 261, Step D. Theproduct is a 3:2 mixture of diastereomers at the 2 position.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.42 (0.6H, d, J=2.4 Hz), 8.37 (1H, d, J=2.2 Hz), 8.22 (0.6 H, d, J=2.0 Hz), 7.91 (1 H, d, J=2.0 Hz),7.35 (0.6 H, t, J=2.1 Hz), 7.23-7.27 (1.3 H, m), 7.16-7.23 (3 H, m),7.08 (1.3 H, d, J=8.6 Hz), 6.90 (2 H, d, J=8.6 Hz), 5.80 (0.6 H, d,J=3.9 Hz), 5.74 (1 H, d, J=4.4 Hz), 3.67-3.73 (0.6 H, m), 3.60 (1 H,ddd, J=9.3, 6.4, 4.6 Hz), 2.96-3.10 (1 H, m), 2.74-2.84 (0.6 H, m), 2.69(1 H, ddd, J=14.4, 9.0, 8.1 Hz), 2.30-2.39 (0.6 H, m), 2.18 (0.6 H, ddd,J=13.8, 9.2, 4.4 Hz), 1.76-1.86 (1 H, m), 1.44 (1.8 H, d, J=7.1 Hz),1.42 (3 H, d, J=6.6 Hz).

Step F.(3S,5R,6R)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-pyran-2-oneand(3R,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-pyran-2-one

The mixture of diastereomers of(5R,6R)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-pyran-2-oneand(5S,6S)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-pyran-2-one(Example 400, Step E, 12.2 g, 36.28 mmol) was converted to the titlecompounds by the procedure described in Example 261, Step E.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.44 (1 H, d, J=2.2 Hz), 8.11 (1 H,d, J=2.0 Hz), 7.18-7.24 (2 H, m), 7.07 (1 H, t, J=2.1 Hz), 6.62-6.67 (2H, m), 5.82 (1 H, ddt, J=17.1, 9.9, 7.4 Hz), 5.71 (1 H, d, J=5.1 Hz),5.13-5.23 (2 H, m), 3.85 (1 H, dt, J=11.7, 4.7 Hz), 2.48-2.66 (2 H, m),1.93-2.07 (2 H, m), 1.42 (3 H, s).

Step G.(S)-2-((2R,3R)-3-(4-Chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropyl)-N—((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamideand(R)-2-((2S,3S)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropyl)-N—((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide

The racemic mixture of(3S,5R,6R)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-pyran-2-oneand(3R,5S,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyltetrahydro-2H-pyran-2-one(Example 400, Step F, 12.4 g, 33.0 mmol;) was converted to the titlecompounds by the procedure described in Example 261, Step G.

Mass Spectrum (ESI) m/z=465.2 [M+H]⁺.

Step H.(3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

The mixture of diastereomers of(S)-2-((2R,3R)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropyl)-N—((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamideand(R)-2-((2S,3S)-3-(4-chlorophenyl)-2-(5-chloropyridin-3-yl)-3-hydroxypropyl)-N—((S)-1-hydroxybutan-2-yl)-2-methylpent-4-enamide(Example 400, Step G, 6.34 g,) was combined in DCM (68 ml) andtriethylamine (13.3 ml, 95 mmol). After cooling in an ice bath,trimethylamine hydrochloride (1.953 g, 20.43 mmol) was added.4-Methylbenzenesulfonic anhydride (17.78 g, 54.5 mmol) was added slowlyas a solid, keeping the temperature below 10° C. The brownish coloredsolution was allowed to slowly warm to room temperature, and thenstirred over night. The next day more trimethyl amine hydrochloride(0.271 mg, 2.91 mmol) was added and the solution was stirred for anotherday. The reaction was quenched with ice water. The layers werepartitioned and the aqueous layer was washed with DCM. The combinedorganics were dried over MgSO₄, filtered, and concentrated to provide abrown oil. The oil was dissolved in MeCN (100 ml) and then heated to 60°C. for 4 hours. The solution was concentrated and the residue dissolvedin 100 ml of DCM. To this was added 100 ml of sat. NaHCO₃ and thebiphasic solution was stirred at rt. for 5 days. The solution waspartitioned and the aqueous layer was washed with DCM. The organics weredried over MgSO₄, filtered and concentrated. The product was purified bysilica gel chromatography to give(3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-O-14S)-1-hydroxybutan-2-O-3-methylpiperidin-2-oneas the second eluting diastereomer.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (1 H, d, J=2.0 Hz), 7.91 (1 H,d, J=1.5 Hz), 7.35 (1 H, t, J=1.8 Hz), 7.26 (1 H, br s), 7.00 (2 H, brd, J=6.8 Hz), 5.78-5.94 (1 H, m), 5.15-5.24 (2 H, m), 4.45 (1 H, d,J=10.3 Hz), 3.59-3.73 (2 H, m), 3.13-3.27 (3 H, m), 2.62 (2 H, d, J=7.6Hz), 2.02-2.11 (1 H, m), 1.85-2.00 (2 H, m), 1.40-1.52 (1 H, m), 1.30 (3H, s), 0.66 (3 H, t, J=7.5 Hz). Mass Spectrum (ESI) m/z=447.2 [M+H]⁺.

Step I.(3S,5S,6R,8S)-8-allyl-5-(4-chlorophenyl)-6-(5-chloropyridin-3-yl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-iummethanesulfonate

The title compound was prepared from(3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 400, Step H) by a procedure similar to the one described inExample 344, Step A. Mass Spectrum (ESI) m/z=429.2 [M]⁺.

Step J.(3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methylpiperidin-2-one

(3S,5S,6R,8S)-8-allyl-5-(4-chlorophenyl)-6-(5-chloropyridin-3-yl)-3-ethyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium methanesulfonate (Example 400, Step I, 0.188g, 0.358 mmol) was converted to the title compound by a proceduresimilar to the one described in Example 340 using cyclopropane sulfinicacid, sodium salt (Oakwood Products, West Columbia, S.C.).

MS (ESI) m/z=535.1 [M+H]⁺.

Step K.2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclopropylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a solution of(3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-O-14S)-1-(cyclopropylsulfonyl)butan-2-O-3-methylpiperidin-2-one(Example 400, Step J, 0.06 g, 0.112 mmol) in DCM (2.241 ml) was addedacetic acid (0.160 ml, 2.80 mmol) and tetrabutylammonium chloridehydrate (3.32 mg, 0.011 mmol). The solution was cooled in an ice bath. Asolution of potassium permanganate (0.053 g, 0.336 mmol) in 1 ml ofwater was prepared and added dropwise to the above solution (rinsed with1 ml of water). The purple solution was stirred in the ice bath for 30minutes and then allowed to warm to room temperature and left overnight.The next day a solution of sodium bisulfite (10% in water) was added.The pH of the aq. layer was adjusted to 2 with 30% H₂SO₄ in water. Thelayers were partitioned and then the aqueous was washed with DCMfollowed by 10% iPrOH/DCM. The combined organics were concentrated undervacuum. The product was purified by silica gel chromatography to providethe title compound as a white solid.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.38 (1 H, d, J=2.2 Hz), 8.00 (1 H,d, J=1.7 Hz), 7.67 (1 H, t, J=2.0 Hz), 7.26 (2 H, br s, overlaps withsolvent), 7.17 (2 H, br s), 4.99 (1 H, d, J=11.0 Hz), 4.28 (1 H, dd,J=13.4, 11.2 Hz), 3.51 (1 H, ddd, J=13.6, 11.1, 2.4 Hz), 3.30 (1H, t,J=10.0 Hz), 2.89-2.97 (2H, m), 2.78 (1H, d, J=13.7 Hz), 2.38-2.46 (1H,m), 2.19-2.26 (1H, m), 2.03-2.14 (1 H, m), 1.85-1.93 (1 H, m), 1.46-1.53(1 H, m), 1.44 (3 H, s), 1.27 (2 H, m, J=5.6 Hz), 1.07-1.11 (2 H, m),0.43 (3 H, t, J=7.6 Hz) Mass Spectrum (ESI) m/z=553.0 [M+H]⁺.

Example 4012-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.2-(3S,5R,6S)-3-Allyl-1-((S)-1-(tert-butylthio)butan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methylpiperidin-2-one

(3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 400, Step H, 0.2 g, 0.447 mmol) was converted to the titlecompounds as a clear film (0.145 g, 62%) by the procedure described inExample 339, Step B using an equivalent of 2-methylpropanethiol.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (1 H, d, J=2.2 Hz), 7.98 (1 H,d, J=1.7 Hz), 7.41 (1 H, t, J=2.1 Hz), 7.24 (2 H, br d, J=8.3 Hz), 6.99(2 H, br d, J=6.6 Hz), 5.87 (1 H, m), 5.13-5.23 (2 H, m), 4.65 (1 H, d,J=10.8 Hz), 3.51 (1 H, t, J=11.4 Hz), 3.19 (1 H, ddd, J=13.7, 10.8, 2.9Hz), 2.63-2.74 (1 H, m), 2.53-2.62 (3 H, m), 2.16 (1 H, t, J=13.6 Hz),2.08 (1 H, m, J=14.2, 8.8, 7.3 Hz), 1.88 (1 H, dd, J=13.4, 3.2 Hz),1.51-1.60 (1 H, m), 1.36 (9 H, br s), 1.31 (3 H, br s), 0.49 (3 H, t,J=7.6 Hz). Mass Spectrum (ESI) m/z=519.2 [M+H]⁺.

Step B.2-((3R,5R,6S)-1-((S)-1-(tert-Butylsulfonyl)butan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

A solution of(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butylthio)butan-2-yl)-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methylpiperidin-2-one(Example 401, Step A, 0.147 g, 0.283 mmol;) with acetic acid (0.972 mL,16.98 mmol) and tetrabutylammonium chloride hydrate (8.37 mg, 0.028mmol) in 4 ml of DCM was cooled in an ice bath. A solution of potassiumpermanganate (0.268 g, 1.698 mmol) in 3 mL of water was added. Thepurple solution was stirred while cooling with an ice bath and allowedto warm to room temperature over 2 hours. Aq. NaS₂O₃ solution was addedalong with additional DCM. After filtering the solution through filterpaper the filtrate was partitioned and then the aq. layer was washedwith DCM. The combined organics were dried over Na₂SO₄ and concentrated.The product was purified by silica gel chromatography followed bypreparatory HPLC (Agilent column, EXTEND C₁₈ PrepHT, 5 uM, 30×250 mm)eluting with a gradient of 20% MeCN/H₂O/0.1% TFA to 80% MeCN/H₂O/0.1%TFA over 25 minutes. The fractions containing the product were combined,frozen in a acetone/dry ice bath and the solvents were removed on alyophilizer to provide the title compound as an off-white solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 12.38 (1 H, br s), 8.42 (1 H, d, J=2.2Hz), 8.02 (1 H, d, J=1.7 Hz), 7.57 (1 H, t, J=2.0 Hz), 7.11-7.47 (4 H,m), 4.83 (1 H, d, J=11.0 Hz), 3.84 (1 H, dd, J=13.0, 10.5 Hz), 3.47-3.57(1 H, m), 3.13 (1 H, br s), 3.05 (1 H, d, J=12.5 Hz), 2.91 (1 H, d,J=13.9 Hz), 2.13-2.23 (1 H, m), 2.03-2.13 (2 H, m), 1.81-1.97 (1 H, m),1.43-1.53 (1 H, m), 1.33 (9 H, s), 1.26 (3 H, s), 0.33 (3 H, t, J=7.6Hz). Mass Spectrum (ESI) m/z=569.2 [M+H]⁺.

Example 4022-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.N—((S)-2-((3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclopropanesulfonamide

(3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 400, Step H, 0.076 g, 0.170 mmol) was converted to the titlecompound by a procedure similar to the one described in Example 272,Step A, using cyclopropanesulfonamide.

MS (ESI) m/z=550.2 [M+H]⁺.

Step B.2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-(cyclopropanesulfonamido)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

N—((S)-2-((3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-1-yl)butyl)cyclopropanesulfonamide(Example 402, Step A, 0.073 g, 0.133 mmol) was converted to the titlecompound by a procedure similar to the one described in Example 400,Step K.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.46 (1 H, d, J=1.7 Hz), 8.17 (1 H,br s), 7.75 (1 H, s), 7.25 (2 H, br s, overlaps with solvent), 7.02-7.18(2 H, m), 5.08 (1 H, br s), 4.92 (1 H, d, J=11.0 Hz), 3.78 (1 H, br s),3.46-3.56 (1 H, m), 3.14 (1 H, dt, J=14.2, 4.5 Hz), 3.02 (1 H, br s),2.77-2.95 (2 H, m), 2.43-2.50 (1 H, m), 2.36 (1 H, t, J=13.8 Hz), 2.00(1 H, dd, J=13.7, 2.7 Hz), 1.79-1.89 (1 H, m), 1.50-1.59 (1 H, m), 1.48(3 H, s), 1.15-1.20 (2 H, m), 0.98-1.05 (2 H, m), 0.51 (3 H, t, J=7.6Hz). Mass Spectrum (ESI) m/z=568.2 [M+H]⁺.

Example 4032-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

Step A:N—((S)-2-((3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

(3S,5R,6S)-3-Allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 400, Step H, 0.1 g, 0.224 mmol) was converted to the titlecompound by a procedure similar to the one described in Example 272,Step A using N-methylcyclopropanesulfonamide.

MS (ESI) m/z=564.2 [M+H]⁺.

Step B.2-((3R,5R,6S)-6-(4-Chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid

N—((S)-2-((3S,5R,6S)-3-allyl-6-(4-chlorophenyl)-5-(5-chloropyridin-3-yl)-3-methyl-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 403, Step A, 0.090 g, 0.159 mmol) was converted to the titlecompound by a procedure similar to the one described in Example 400,Step K.

¹H NMR (500 MHz, Acetone-d₆) δ ppm 8.38 (1 H, d, J=1.7 Hz), 8.11 (1 H,s), 7.68 (1 H, t, J=2.0 Hz), 7.21-7.43 (4 H, m), 4.92 (1 H, d, J=10.8Hz), 4.02-4.21 (1 H, m), 3.57 (1H, ddd, J=13.8, 10.9, 2.9 Hz), 2.99 (1H, d, J=14.2 Hz), 2.91-2.96 (5 H, m), 2.76 (1 H, d, J=14.2 Hz),2.53-2.62 (1 H, m), 2.39 (1 H, t, J=13.7 Hz), 2.19 (1 H, dd, J=13.4, 2.9Hz), 1.75-1.86 (1 H, m), 1.66-1.74 (1 H, m), 1.42 (3 H, s), 0.96-1.12 (4H, m), 0.52 (3 H, t, J=7.6 Hz). Mass Spectrum (ESI) m/z=582.0 [M+H]⁺.

Example 4042-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-(ethylthio)butan-2-yl)-3-methylpiperidin-2-one

(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 121, Step L, 100 mg, 0.224 mmol) was azeotroped three times inbenzene on a rotary evaporator. The residue was dissolved in toluene andtransferred to a reaction vessel. The vessel was flushed with argon.Ethanethiol (33.1 μl, 0.447 mmol) was added followed bycyanomethylenetributylphosphorane (216 μl, 0.894 mmol). The vessel wassealed and the solution was heated to 100° C. for 4 h. The reactionmixture was diluted with DCM (10 ml) and Si-maleimide (Silicycle, 2.1 g;0.66 mmol/g; 40-63 microns) was added to scavenge excess thiol. Afterstirring for about 1 h, the mixture was filtered and the silica gel wasrinsed with DCM. The filtrate was concentrated on a rotary evaporator.The residue was dissolved in DCM and loaded directly onto a dry 12 ggold-capped Redisep® column (Teledyne Isco, Lincoln, Nebr.). The columnwas eluted with a gradient of 0 to 5% MeOH:DCM. The fractions containingthe desired product were combined and concentrated to afford the titlecompound as a colorless film.

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-(ethylsulfonyl)butan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-1-((S)-1-(ethylthio)butan-2-yl)-3-methylpiperidin-2-one(Example 404, step A) was converted to the title compound by a proceduresimilar to the one described in Example 395, Step C.

¹H NMR (400 MHz, CDCl₃) δ ppm 8.65 (d, J=2.3 Hz, 1 H), 7.48 (dd, J=2.4,8.1 Hz, 1 H), 7.16-7.07 (m, 2 H), 6.98 (s, 1 H), 6.92-6.86 (m, 2 H),5.00 (d, J=10.2 Hz, 1 H), 4.25-4.16 (m, 1 H), 3.57-3.46 (m, 1 H), 3.26(br s, 1H), 3.15 (d, J=15.3 Hz, 1 H), 3.10-3.01 (m, 2 H), 2.91 (d,J=15.5 Hz, 1 H), 2.80 (d, J=11.7 Hz, 1 H), 2.36 (t, J=13.9 Hz, 1 H),2.04-1.90 (m, 2 H), 1.50-1.40 (m, 7 H), 0.38 (t, J=7.0 Hz, 3 H); MassSpectrum (ESI) m/z=541.2 [M+H]⁺.

Example 4052-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid, TFA salt or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid, TFA Salt

Step A. (S)-tert-Butyl 2-((S)-1-hydroxypropyl)morpholine-4-carboxylateand (R)-tert-Butyl 2-((S)-1-hydroxypropyl)morpholine-4-carboxylate and(S)-tert-Butyl 2-((R)-1-hydroxypropyl)morpholine-4-carboxylate and(R)-tert-Butyl 2-((R)-1-hydroxypropyl)morpholine-4-carboxylate

To a solution of (rac)-tert-butyl 2-formylmorpholine-4-carboxylate(0.996 g, 4.63 mmol) (Tyger Scientific Inc., Ewing, N.J., USA) in THF(25 mL) at RT was added a solution of 3.0 M ethylmagnesium bromide indiethyl ether (1.851 mL, 5.55 mmol) dropwise. After 4 h, the mixture wasquenched with sat. aq. NH₄Cl solution. The mixture was extracted withEtOAc. The organic layers were washed with brine, dried over Na₂SO₄,filtered and the filtrate was concentrated to afford a mixture of thetitle compounds.

Step B. (S)-tert-butyl2-((S)-1-(((4-bromophenyl)sulfonyl)oxy)propyl)morpholine-4-carboxylateand (R)-tert-butyl2-((S)-1-(((4-bromophenyl)sulfonyl)oxy)propyl)morpholine-4-carboxylateand (S)-tert-butyl2-((R)-1-(((4-bromophenyl)sulfonyl)oxy)propyl)morpholine-4-carboxylateand (R)-tert-butyl2-((R)-1-(((4-bromophenyl)sulfonyl)oxy)propyl)morpholine-4-carboxylate

To a solution of the mixture of diastereomers from Example 405, step A(509 mg, 2.075 mmol;) in DCM (6.9 mL) was added DMAP (558 mg, 4.56 mmol)and 4-bromobenzenesulfonyl chloride (795 mg, 3.11 mmol). After stirringfor 18 h, the mixture was partitioned between EtOAc and water. Theorganic layer was washed with brine, dried over Na₂SO₄, filtered and thefiltrate was concentrated. The residue was purified by flashchromatography on silica gel (40 g column, eluent: 5 to 30%EtOAc/hexanes) to afford a mixture of the title compounds.

Step C. (S)-tert-butyl2-((S)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)propyl)morpholine-4-carboxylateand (R)-tert-butyl2-((S)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)propyl)morpholine-4-carboxylateand (S)-tert-butyl2-((R)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)propyl)morpholine-4-carboxylateand (R)-tert-butyl2-((R)-1-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)propyl)morpholine-4-carboxylate

The diastereomeric brosylates (Example 404, Step B, 124 mg, 0.267 mmol)were dissolved in toluene and concentrated in vacuo twice. Dioxane (1mL) was added followed by sodium tert-butoxide (25.7 mg, 0.267 mmol).The mixture was heated at 85° C. for 2 days. The mixture was partitionedbetween EtOAc and dilute aq. NH₄Cl solution. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by flash chromatography on silicagel (4 g column, eluent: 5 to 35% EtOAc/hexanes) to afford a mixture ofthe title compounds.

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((S)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid, TFA salt or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-1-((R)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid, TFA salt

The mixture of diastereomers obtained in Example 404, Step C (100 mg,0.166 mmol) was dissolved in THF (1 mL). Water (about 0.5 mL) was addeduntil the solution became cloudy. t-BuOH was added until the solutionbecame clear. NMO (29.2 mg, 0.249 mmol) was added followed by 4% aq.osmium tetroxide solution (5.28 μl, 0.831 μmol). After stirring for 18h, another 3 drops of 4% aq. OsO₄ solution was added. After stirring for4 h, 0.20 mL of Jones Reagent was added. After 2 days, the mixture waspartitioned between aq. NaHCO₃ and DCM. The aqueous layer was extractedwith DCM and EtOAc. The combined organic layers were washed with brine,dried over Na₂SO₄, filtered and the filtrate was concentrated. Themixture was stirred in DCM (3 mL) and TFA (1 mL, 12.98 mmol) for 25minutes and was concentrated. The residue was purified by reversed phasepreparative HPLC (column: Gemini-NX C₁₈ 5 um column; Phenomonex,Torrance, Calif.; eluent: 30 to 50% MeCN+0.1% TFA in water+0.1% TFA over20 minutes) to provide three of the four possible diasteromers of thetitle compound. The first eluting of these diastereomers is Example 405:

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.33 (t, J=7.5 Hz, 3 H) 1.30-1.42(m, 1 H) 1.47 (s, 3 H) 1.68-1.82 (m, 1 H) 1.82-1.91 (m, 1 H) 2.19-2.26(m, 2 H) 2.56-2.64 (m, 3 H) 2.68-2.87 (m, 1 H) 3.03 (d, J=12.3 Hz, 1 H)3.07-3.33 (m, 2 H) 3.54-3.76 (m, 1 H) 3.76-3.99 (m, 1 H) 4.25-4.36 (m, 1H) 4.51 (d, J=10.6 Hz, 1 H) 4.57-4.71 (m, 1 H) 6.70 (d, J=7.8 Hz, 1 H)7.00 (t, J=1.9 Hz, 1 H) 7.14 (t J=7.6 Hz, 1 H) 7.21 (d, J=8.0 Hz, 1 H)7.28-7.32 (m, 4 H) 8.13 (br s, 1 H) 11.54 (br s, 1 H). Mass Spectrum(ESI) m/z=519.1 (M+1).

Example 4062-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid, TFA salt or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid, TFA Salt

Further elution of the HPLC column in Example 405, Step D provided oneof the title compounds as the second eluting isomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93-1.11 (m, 3 H) 1.39-1.58 (m, 3H) 1.62-1.78 (m, 1 H) 1.79-1.92 (m, 1 H) 1.93-2.02 (m, 1 H) 2.16-2.29(m, 1 H) 2.55-2.70 (m, 2 H) 2.73-3.00 (m, 2 H) 3.03-3.24 (m, 2 H)3.26-3.44 (m, 2 H) 3.45-3.54 (m, 1 H) 3.60-3.67 (m, 1 H) 3.75-3.97 (m, 1H) 4.30-4.47 (m, 2 H) 6.73 (d, J=7.4 Hz, 1 H) 6.98 (br s, 1 H) 7.11 (t,J=8.0 Hz, 1 H) 7.17 (d, J=8.0 Hz, 1 H) 7.23-7.33 (m, 4 H) 8.99 (br s, 1H) 9.96 (br s, 1 H).

Mass Spectrum (ESI) m/z=519.1 (M+1).

Example 4072-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((R)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid, TFA salt or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((R)-1-((S)-morpholin-2-yl)propyl)-2-oxopiperidin-3-yl)aceticacid, TFA Salt

Further elution from the HPLC column in Example 405 provided the other(relative to Example 406) of the title compounds as the third elutingisomer.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.10 (t, J=7.5 Hz, 3 H) 1.47 (s, 3H) 1.83-1.93 (m, 1 H) 1.98-2.09 (m, 2 H) 2.15-2.32 (m, 2 H) 2.59-2.64(m, 1 H) 2.66-2.72 (m, 2 H) 2.73-2.85 (m, 2 H) 3.23 (d, J=13.3 Hz, 1 H)3.43 (t, J=12.2 Hz, 1 H) 3.66 (t, J=11.7 Hz, 1 H) 3.77-3.92 (m, 2 H)4.34 (t, J=8.1 Hz 1 H) 4.41 (d, J=10.6 Hz, 1 H) 6.73 (d, J=7.6 Hz 1 H)6.96 (br s, 1 H) 7.08 (t, J=8.0 Hz, 1 H) 7.13 (d, J=8.0 Hz, 1 H)7.25-7.42 (m, 4 H) 9.16 (br s, 1 H) 9.43 (br s, 1 H). Mass Spectrum(ESI) m/z=519.1 (M+1).

Example 4082-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)aceticacid

Step A.(3R,5R,6S)-3-Allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperidin-2-oneand(3S,5R,6S)-3-Allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperidin-2-one

The title compound was obtained from(3R,5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 127, Step A) and 1-((2-iodoethoxy)methyl)-4-methoxybenzene [J.Am. Chem. Soc., 124, 8206-8219, (2002)] by a procedure similar to theone described in Example 69, Step A. Purification of the residue byflash chromatography on silica gel (eluent: 0 to 20% EtOAc/hexane,gradient elution over 30 min) provided the desired products as a mixtureof C3 epimers.

Mass Spectrum (ESI) m/z=834.4 (M+1) and 856.4 (M+Na).

Step B.(3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperidin-2-one

To a solution of a mixture of(3R,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperidin-2-oneand(3S,5R,6S)-3-allyl-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-((4-methoxybenzyl)oxy)ethyl)piperidin-2-one(19.23 g, 23.03 mmol; Example 408, Step A) in THF (92 ml) at rt wasslowly added a solution of TBAF (1.0M in THF, 34.5 ml, 34.5 mmol). Thereaction was monitored by LCMS, and when judged complete wasconcentrated under reduced pressure (no heat), then diluted in 400 mL ofEtOAc. HCl (1N, 150 ml) was added. The layers were separated and theaqueous layer was extracted with EtOAc. The combined organics werewashed several times with water, dried over MgSO₄, filtered, and thefiltrate was concentrated. Purification by chromatography on silica gel(eluent: 10 to 20% EtOAc/hexane, gradient elution over 30 min) providedthe title compound along with its C3 epimer as a clear, colorless foam.Individual steroisomers were separated by chiral HPLC (flowrate: 120ml/min, 1 g per injection, on a Chiralcel® OD-H 5 cm I.D.×50 cm, 20 μmcolumn; Daicel Chemical Industries LTD, using 6% isopropylalcohol/hexane as the eluent) to give the title compound as the firsteluting isomer (t_(R)=11-23 min) as a clear, viscous oil.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.61 (t, J=7.5 Hz, 3 H) 1.33 (ddd,J=13.9, 7.8, 5.8 Hz, 1 H) 1.79 (dd, J=13.7, 2.9 Hz, 1 H) 1.94 (dt,J=14.8, 7.5 Hz, 1 H) 2.02 (s, 1 H) 2.11-2.21 (m, 3 H) 2.26 (t, J=13.6Hz, 1 H) 2.77 (dd, J=13.3, 6 Hz, 1 H) 3.12 (br s, 1 H) 3.22 (ddd,J=13.5, 10.6, 2.8 Hz, 1 H) 3.58 (d, J=3.7 Hz, 2 H) 3.70 (t, J=6.4 Hz, 2H) 3.81 (s, 3 H) 4.35 (d, J=10.5 Hz, 1 H) 4.37-4.50 (m, 2 H) 5.12-5.22(m, 2 H) 5.75-5.86 (m, 1 H) 6.64 (d, J=7.8 Hz, 1 H) 6.85 (m, 2 H) 6.92(s, 2 H) 7.06 (t, J=7.8 Hz, 1 H) 7.10-7.19 (m, 3 H) 7.21 (m, J=8.6 Hz, 2H). Mass Spectrum (ESI) m/z=596.2 (M+H) and 618.2 (M+Na).

Step C.N—((S)-2-((3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-(4-methoxybenzyloxy)ethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

The title compound was prepared from(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-(2-(4-methoxybenzyloxy)ethyl)piperidin-2-one(Example 408, Step B) and N-methylcyclopropanesulfonamide by a proceduresimilar to the one described in Example 201, Step A.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.55 (br s, 3 H) 0.87-0.99 (m, 2 H)1.19 (td, J=5.4, 1.6 Hz, 1 H) 1.48-1.65 (m, 4 H) 1.75 (dd, J=13.7, 3.2Hz, 1 H) 1.85 (dquin, J=14.7, 7.5 Hz, 1 H) 2.02 (s, 1 H) 2.06-2.11 (m, 1H) 2.16-2.30 (m, 3 H) 2.52 (br s, 2 H) 2.87 (s, 1 H) 2.89 (s, 3 H) 3.20(ddd, J=13.6, 10.7, 3.1 Hz, 1 H) 3.71 (t, J=7Hz, 2 H) 3.81 (s, 3 H)4.41-4.50 (m, 2 H) 4.66 (br s, 1 H) 5.04-5.12 (m, 2 H) 5.76-5.88 (m, 1H) 6.83 (d, J=6.9 Hz, 1 H) 6.85-6.90 (m, 2 H) 6.91 (s, 1 H) 7.08-7.20(m, 4 H) 7.25 (s, 1H). Mass Spectrum (ESI) m/z=713.2 (M+1) and 735.2(M+Na).

Step D.N—((S)-2-((3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-hydroxyethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

To a solution of 3.09 g (4.33 mmol)N—((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-(4-methoxybenzyloxy)ethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 408, step C) in a mixture of DCM (82 mL) and water (4.56 mL)[18:1] was added 2,6-di-tert-butylpyridine (2.93 mL, 12.99 mmol)followed by DDQ (3.93 g, 17.32 mmol). The reaction mixture was stirredvigorously at ambient temperature for 15 min. The reaction mixture wasdiluted with 150 mL sat. NaHCO₃/brine solution and extracted into 600 mLof ethyl acetate, then 200 mL of EtOAc×2 (precipitate was removed byfiltration). The combined organic layers were dried over MgSO₄, filteredand the filtrate was evaporated. Purification by chromatography onsilica gel (eluent: 50-100%% EtOAc/hexane, gradient elution) providedthe desired product as a foam.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.54 (br s, 3 H) 0.92-1.06 (m, 2 H)1.20 (dd, J=4.8, 2.1 Hz, 2 H) 1.27 (t, J=7.2 Hz, 1 H) 1.53-1.66 (m, 1 H)1.66-1.76 (m, 2 H) 1.95 (dt, J=14.9, 7.6 Hz, 1 H) 2.23-2.39 (m, 3 H)2.59 (br s, 1 H) 2.87 (s, 1 H) 2.90 (s, 3 H) 3.17 (ddd, J=13.8, 10.6,3.1 Hz, 1 H) 3.77 (dt, J=12.0, 4.6 Hz, 1 H) 4.10-4.20 (m, 1 H) 4.71 (brs, 1 H) 5.07-5.21 (m, 2 H) 5.65-5.80 (m, 1 H) 6.90 (br s, 1H) 6.96 (s, 1H) 7.11-7.16 (m, 2 H) 7.22 (br s, 1 H) 7.26 (br s, 2 H). Mass Spectrum(ESI) m/z=593.2 (M+1) and 615.2 (M+Na).

Step E.N—((S)-2-((3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

To a solution of 2.52 g (4.25 mmol)N—((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-hydroxyethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 408, Step D), DMAP (0.026 g, 0.212 mmol), and imidazole (0.723g, 10.61 mmol) in DCM (16.98 mL) at 0° C. was added slowly by syringeTIPS-Cl (1.17 mL, 5.52 mmol). The reaction was stirred at ambienttemperature, with addition of reagents until reaction was judgedcomplete by LCMS and TLC. The reaction mixture was quenched by additionof 6 mL of MeOH, then extracted with DCM (70 mls×2). The combinedorganics were washed with water (30 mL), satd. aq.NH₄Cl solution (20mL), dried over Na₂SO₄, filtered and the filtrate was concentrated.Purification by chromatography on silica gel (eluent: 0 to 40%EtOAc/DCM, gradient elution) provided the title compound as a clear,colorless oil. Mass Spectrum (ESI) m/z=749.4 (M+1).

Step F.N—((S)-2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-oxoethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

N—((S)-2-((3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 408, Step E) was treated by a procedure similar to the onedescribed in Example 91, Step E. Purification by chromatography onsilica gel (12 g SiO₂, eluent: 0 to 30% EtOAc/hexane, gradient elution)provided the title compound as a clear oil.

Mass Spectrum (ESI) m/z=751.2 (M+1)

Step G.N—((S)-2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-morpholinoethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

N—((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-oxoethyl)-3-(2-((triisopropylsilyl)oxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 408, Step F) and morpholine were combined according to aprocedure similar to the one described in Example 91, Step F.Purification by chromatography on silica gel (eluent: 50 to 100%EtOAc/DCM, gradient elution over 15 min) provided the title compound asa clear, colorless glass.

Mass Spectrum (ESI) m/z=822.4 (M+1)

Step H.N—((S)-2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-hydroxyethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

N—((S)-2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-morpholinoethyl)-2-oxo-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 408, Step G) was treated according to a procedure similar tothe one described in Example 69, step D to afford the title compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.53 (t, J=7.6 Hz, 3 H) 1.02-1.06(m, 1 H) 1.06-1.14 (m, 1 H) 1.14-1.22 (m, 1 H) 1.22-1.31 (m, 1 H) 1.49(d, J=7.1 Hz, 1 H) 1.64 (ddd, J=14.2, 7.8, 3.7 Hz, 3 H) 1.77-1.98 (m, 4H) 1.98-2.02 (m, 1 H) 2.02-2.06 (m, 3 H) 2.25-2.43 (m, 4 H) 2.44-2.50(m, 1 H) 2.61 (dd, J=13.8, 1.8 Hz, 1 H) 2.79-2.89 (m, 3 H) 2.89-3.06 (m,2 H) 3.12-3.26 (m, 1 H) 3.39-3.50 (m, 2 H) 3.50-3.56 (m, 1 H) 3.61 (d,J=12.7 Hz, 1 H) 3.75-3.90 (m, 1 H) 3.92-4.09 (m, 3 H) 4.14-4.38 (m, 2 H)4.48 (br s, 1 H) 4.68 (d, J=10.5 Hz, 1 H) 6.82-6.93 (m, 1 H) 6.98 (s, 2H) 7.08-7.21 (m, 2 H) 12.31 (br s, 1 H).

Mass Spectrum (ESI) m/z=666.2 (M+1)

Step I.2-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)aceticacid

N—((S)-2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-hydroxyethyl)-3-(2-morpholinoethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 408, Step H) was treated according to a procedure similar tothe one described in Example 69, step E. The reaction (using 4 eq. ofJones Reagent) went to completion in less than 2 minutes at 0° C., afterwhich it was quenched with MeOH (10 eq) and diluted in EtOAc. Thesolution was decanted from insoluble material, washed with aq. NaHCO₃solution, dried over MgSO₄, filtered and concentrated under reducedpressure. Purification by reversed phase prep. HPLC (Sunfire Prep C₁₈OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40% MeCNin water to 75% MeCN in water over a 30 min period, where both solventscontain 0.1% TFA) provided the title compound as the TFA salt.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.49 (t, J=7.5 Hz, 3 H) 0.96-1.16(m, 3 H) 1.17-1.28 (m, 1 H) 1.56-1.67 (m, 1 H) 1.85 (dt, J=15.2, 7.7 Hz,1 H) 2.00 (dd, J=13.6, 3.1 Hz, 1 H) 2.06-2.16 (m, 1 H) 2.22-2.41 (m, 3H) 2.57-2.66 (m, 1 H) 2.71 (br s, 1 H) 2.85 (s, 3 H) 2.87-2.96 (m, 3 H)2.99 (br s, 1 H) 3.03 (br s, 1 H) 3.16-3.27 (m, 1 H) 3.34 (br s, 1 H)3.52-3.66 (m, 2 H) 3.70 (d, J=12 Hz, 1 H) 3.79-3.96 (m, 2 H) 4.03 (d,J=11 Hz, 2 H) 4.38 (br s, 1 H) 4.68 (d, J=10.5 Hz, 1 H) 6.84-6.94 (m, 2H) 6.98 (s, 2 H) 7.10-7.17 (m, 2 H) 7.22-7.27 (m, 1 H) 8.42 (br s, 3 H)11.01 (br s, 1 H). Mass Spectrum (ESI) m/z=680.2 (M+1).

Examples 409-411 were prepared fromN—((S)-2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-(2-oxoethyl)-3-(2-(triisopropylsilyloxy)ethyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 408, Step F) by procedures similar to those described inExample 408, substituting morpholine in step G with the appropriateamine.

Example R= 409

410

411

Example 4092-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothiomorpholino)ethyl)-1-4S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid, TFA Salt

¹H NMR (500 MHz, CD₃OD) δ ppm 0.51 (t, J=7.5 Hz, 3 H) 1.00-1.07 (m, 1 H)1.07-1.19 (m, 2 H) 1.21-1.30 (m, 2 H) 1.54-1.68 (m, 1 H) 1.79-1.91 (m, 1H) 1.95 (dd, J=13.7, 2.7 Hz, 1 H) 2.26 (t, J=13.5 Hz, 2 H) 2.29-2.39 (m,2 H) 2.61 (d, J=13 Hz, 1 H) 2.73 (br s, 1 H) 2.79 (d, J=13.7 Hz, 1 H)2.84 (s, 3 H) 2.88-2.96 (m, 1 H) 3.20 (ddd, J=13.4, 10.7, 3.1 Hz, 1 H)3.52 (br s, 3 H) 3.57 (d, J=8.3 Hz, 3 H) 3.86 (br s, 4 H) 4.43 (t,J=12.1 Hz, 1 H) 4.70 (d, J=10.8 Hz, 1 H) 6.87 (d, J=7.1 Hz, 1 H) 6.99(s, 3 H) 7.12-7.21 (m, 2 H) 7.27 (br s, 1 H). Mass Spectrum (ESI)m/z=728.2 (M+1).

Example 4102-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-(pyrrolidin-1-yl)ethyl)piperidin-3-yl)aceticacid, HCl Salt

¹H NMR (500 MHz, CD₃OD) δ ppm 0.52 (t, J=7.6 Hz, 3 H) 0.98-1.21 (m, 4 H)1.69 (ddd, J=14.2, 7.6, 4.9 Hz, 1 H) 1.77-1.92 (m, 1 H) 1.92-2.10 (m, 3H) 2.10-2.24 (m, 3 H) 2.27-2.42 (m, 2 H) 2.54-2.62 (m, 1 H) 2.76 (dd,J=14.2, 2 Hz, 1 H) 2.79-2.87 (m, 1 H) 2.88 (s, 3 H) 2.91-3.03 (m, 1 H)3.12 (dtd, J=11.3, 8.0, 3.2 Hz, 2 H) 3.33-3.46 (m, 2 H) 3.63 (ddd,J=12.9, 8.9, 7.1 Hz, 1 H) 3.66-3.77 (m, 2 H) 4.39 (t, J=10.9 Hz, 1 H)4.81 (d, J=11 Hz, 1 H) 6.94-7.02 (m, 1 H) 7.08 (s, 1 H) 7.12-7.24 (m, 3H) 7.32 (d, J=7.8 Hz, 2 H). Mass Spectrum (ESI) m/z=728.2 (M+1).

Example 4112-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-3-(2-(dimethylamino)ethyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid, HCl Salt

¹H NMR (500 MHz, CD₃OD) δ ppm 0.52 (t, J=7.6 Hz, 3 H) 0.98-1.21 (m, 4 H)1.69 (ddd, J=14.3, 7.7, 4.2 Hz, 1 H) 1.76-1.93 (m, 1 H) 1.98 (dd,J=13.7, 3.2 Hz, 1 H) 2.12 (ddd, J=14.5, 7.6, 5 Hz, 1 H) 2.29-2.44 (m, 2H) 2.55-2.66 (m, 1 H) 2.76 (dd, J=14.2, 2 Hz, 1 H) 2.80-2.88 (m, 1 H)2.88-3.06 (m, 11 H) 3.24-3.37 (m, 2 H) 3.42 (ddd, J=13.6, 10.8, 3.1 Hz,1 H) 3.61 (dt, J=13.3, 7.8 Hz, 1H) 4.42 (t, J=11.3 Hz, 1 H) 4.81 (d,J=11 Hz, 1 H) 6.93-7.04 (m, 1 H) 7.09 (s, 1 H) 7.12-7.26 (m, 3 H) 7.32(d, J=7.6 Hz, 2 H). Mass Spectrum (ESI) m/z=638.2 (M+1).

Example 4122-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetamide,HCl Salt

HATU (119 mg, 0.313 mmol) was added to a solution of 83 mg (0.522mmol)of the TFA salt of2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)aceticacid (Example 408, step I) and TEA (72.8 μL, 0.522 mmol) in DMF (2.09mL). The mixture was stirred for 3 min at ambient temperature, then asolution of NH₃ (7M in MeOH, 0.45 mL, 3.13 mmol) was added. The startingmaterial was consumed within minutes. The mixture was concentrated underreduced pressure and purified by reversed phase prep. HPLC (Sunfire PrepC₁₈ OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 40%MeCN in water to 75% MeCN in water over a 30 min period, where bothsolvents contain 0.1% TFA). A few drops of HCl were added prior tolyophilization, so that the title compound was generated as the HClsalt.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 0.55 (t, J=7.6 Hz, 3 H) 0.98-1.09(m, 2 H) 1.09-1.24 (m, 2 H) 1.61-1.78 (m, 1 H) 1.83-1.99 (m, 1 H)2.08-2.17 (m, 1 H) 2.33 (t, J=13.7 Hz, 1 H) 2.46 (ddd, J=15, 8.1, 7.2Hz, 1 H) 2.56-2.64 (m, 1 H) 2.73-2.83 (m, 2 H) 2.83-2.93 (m, 4 H) 2.99(d, J=14.4 Hz, 1 H) 3.11 (td, J=12.1, 3.4 Hz, 1 H) 3.16-3.27 (m, 1 H)3.36-3.51 (m, 2 H) 3.51-3.67 (m, 2 H) 3.67-3.73 (m, 1 H) 3.74-3.88 (m, 2H) 4.13 (t, J=9.8 Hz, 2 H) 4.39 (t, J=12.4 Hz, 1 H) 4.81 (d, J=11 Hz, 1H) 6.89-7.05 (m, 1 H) 7.08 (s, 1 H) 7.11-7.27 (m, 3 H) 7.34 (d, J=7.1Hz, 2 H). Mass Spectrum (ESI) m/z=679.2 (M+1).

Example 4132-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(2-morpholinoethyl)-2-oxopiperidin-3-yl)acetamide,HCl salt

2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(2-(1,1-dioxidothiomorpholino)ethyl)-1-4S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)aceticacid (Example 409) was treated according to a procedure similar to theone described in Example 412 to afford the title compound.

¹H NMR (500 MHz, CD₃OD) δ ppm 0.53 (t, J=7.6 Hz, 3 H) 0.98-1.07 (m, 2 H)1.07-1.16 (m, 1 H) 1.20 (td, J=8.6, 4.4 Hz, 1 H) 1.70 (ddd, J=14.2, 7.8,3.9 Hz, 1 H) 1.91 (dt, J=15, 7.6 Hz, 1 H) 2.01 (dd, J=13.5, 2.9 Hz, 1 H)2.12 (dt, J=14.8, 5.3 Hz, 1 H) 2.32 (t, J=13.7 Hz, 1 H) 2.39-2.51 (m, 1H) 2.59 (dt, J=12.6, 6.4 Hz, 1 H) 2.75-2.87 (m, 3 H) 2.89 (s, 3 H) 2.98(d, J=14.7 Hz, 1 H) 3.37-3.49 (m, 1 H) 3.50-3.65 (m, 5 H) 3.65-3.75 (m,1 H) 3.95 (br s, 4 H) 4.38 (t, J=12 Hz, 1 H) 4.79 (d, J=10.8 Hz, 1 H)7.01 (dd, J=6.5, 2.1 Hz, 1 H) 7.07 (s, 1 H) 7.10-7.26 (m, 3 H) 7.32 (d,J=7.1 Hz, 2 H). Mass Spectrum (ESI) m/z=727.2 (M+1).

Example 414(1R,3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-54S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylicacid and(3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-4S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylicacid

Step A.(3R,5R,6S)-3-Allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one

Lithium bis(trimethylsilyl)amide, (1M solution in toluene, 4.76 mL, 4.76mmol) was added to a solution of(5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one(Example 185, Step C, 2.0 g, 3.17 mmol) and 3-bromopropene (0.274 mL,3.17 mmol) in THF at −78° C. The reaction was warmed to 0° C. andstirred for 2 hours. After recooling to −78° C., a solution of LDA (7.93mmol in THF) followed by 2-(chloromethoxy)ethyltrimethylsilane (0.842mL, 4.76 mmol) was added. The reaction was warmed to 50° C. and stirredfor 1.5 hours. The reaction mixture was diluted with EtOAc and washedwith HCl (1N). The organic extract was washed with satd NaCl and driedover Na₂SO₄. The solution was filtered and concentrated in vacuo. Thecrude material was purified by chromatography on silica gel, elutingwith a gradient of 0% to 20% EtOAc in hexane, to provide(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-oneas the first eluting diastereomer and the title compound as the seconddiastereomer as an oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.07-0.05 (m, 9 H) 0.37 (t, J=7.6Hz, 3 H) 0.91-1.05 (m, 3 H) 1.28-1.46 (m, 2 H) 1.79 (dd, J=13.6, 2.8 Hz,1 H) 1.86 (ddd, J=14.1, 9.3, 7.2 Hz, 1 H) 2.35 (dd, J=13.8, 7.9 Hz, 1 H)2.49-2.65 (m, 2 H) 2.68-2.83 (m, 1 H) 3.02-3.17 (m, 2 H) 3.39-3.53 (m, 2H) 3.59 (td, J=10, 7.0 Hz, 2H) 3.84 (d, J=7.8 Hz, 1 H) 4.08 (t, J=10 Hz,1 H) 4.42 (d, J=10.6 Hz, 1 H) 5.03-5.19 (m, 2 H) 5.76-5.95 (m, 1 H) 6.66(d, J=7.6 Hz, 1 H) 6.92 (t, J=1.8 Hz, 2 H) 6.97-7.10 (m, 3 H) 7.15 (d,J=7.4 Hz, 2 H).

Step B.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one

A 1M solution of TBAF in THF (2.15 mL, 2.15 mmol) was added to asolution of(3S,5R,6S)-3-allyl-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one(Example 414, Step A; 860 mg, 1.074 mmol) in THF. The reaction washeated to reflux for 3 hours. After cooling, it was diluted with EtOAcand washed with HCl (1N in water). The organic extract was washed withsatd NaCl and dried over Na₂SO₄. The solution was filtered andconcentrated to give the crude material as a glass which was purified bychromatography on silica eluting with 20% EtOAc in hexane, to providethe title compound as a solid.

Step C.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)cyclopropanesulfonamide

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-2-one(Example 414, Step B) and N-methylcyclopropanesulfonamide by a proceduresimilar to the one described in Example 201, Step A. The product waspurified by chromatography through a RediSep® pre-packed silica gelcolumn (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradientof 0% to 80% EtOAc in hexane, to provide the title compound as an oil.Mass Spectrum (ESI) m/z=665.2 (M+1).

Step D.N—((S)-2-((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide

A solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)cyclopropanesulfonamide(Example 414, Step C, 1.5 g, 2.253 mmol) in THF was treated with sodiumhydride (60% dispersion in mineral oil, 6.76 mmol) and iodomethane(0.280 ml, 4.51 mmol) at room temperature for 3 hours. The reactionmixture was quenched with HCl (1N) and diluted with DCM. The organicextract was washed with satd NaCl and dried over Na₂SO₄. The solutionwas filtered and concentrated in vacuo to give the crude material as anoil. The product was purified by chromatography through a RediSep®pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.) (4 g),eluting with a gradient of 0% to 80% EtOAc in hexane, to provide thetitle compound as an oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm −0.06-0.03 (m, 9 H) 0.54 (t, J=6.9Hz, 3 H) 0.80-1.03 (m, 5 H) 1.13 (d, J=8.8 Hz, 1 H) 1.14-1.23 (m, 2 H)1.56-1.65 (m, 2 H) 1.75-1.93 (m, 2 H) 2.28 (t, J=4.5 Hz, 1 H) 2.51 (t,J=13.8 Hz, 1 H) 2.60 (d, J=7.4 Hz, 2 H) 3.01 (s, 3 H) 3.20 (ddd, J=13.9,10.8, 3.1 Hz, 1 H) 3.31-3.40 (m, 1 H) 3.40-3.49 (m, 1 H) 3.49-3.60 (m, 1H) 3.79 (d, J=8.6 Hz, 1 H) 4.71 (d, J=10.8 Hz, 1 H) 5.11-5.24 (m, 2 H)5.83-6.00 (m, 1 H) 6.84-6.91 (m, 1 H) 6.94 (s, 1 H) 7.01 (d, J=7.8 Hz, 2H) 7.07-7.16 (m, 2 H) 7.21 (d, J=8.2 Hz, 2 H).

Step E.((3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)methylmethanesulfonate

A solution ofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)piperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(Example 414, Step D, 1.85 g, 2.72 mmol) in DCM was treated with borontrifluoride (diethyl etherate, purified, redistilled, 0.672 ml, 5.44mmol) for 2 hours. The reaction mixture was diluted with DCM and washedwith satd NaCl. The organic extract was dried over Na₂SO₄, filtered andconcentrated in vacuo to give the crude material as an oil. The productwas purified by chromatography on a RediSep® pre-packed silica gelcolumn (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with a gradientof 0% to 80% EtOAc in hexane, to provide the intermediateN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(1.55 g, 2.67 mmol, 98% yield) as an oil which was used directly in thenext reaction.

Methanesulfonyl chloride (0.200 ml, 2.59 mmol) was added to a solutionofN—((S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-(hydroxymethyl)-2-oxopiperidin-1-yl)butyl)-N-methylcyclopropanesulfonamide(1.0 g, 1.725 mmol) and triethylamine (0.480 ml, 3.45 mmol) in DCM. Thereaction was stirred for 2 hours. The reaction mixture was diluted withDCM and washed with HCl (1N) and satd NaCl and dried over Na₂SO₄. Thesolution was filtered and concentrated in vacuo to give the crudematerial as an oil. The product was purified by chromatography through aRediSep® pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)(12 g), eluting with a gradient of 0% to 80% EtOAc in hexane, to providethe title compound as an oil. Mass Spectrum (ESI) m/z=657.2 (M+1).

Step F.43R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-oxoethyl)piperidin-3-yl)methylmethanesulfonate

Ozone was bubbled through a solution of((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxopiperidin-3-yl)methylmethanesulfonate (Example 414, Step E, 1.12 g, 1.703 mmol) in 10%MeOH-DCM at −78° C. until a blue color developed. The reaction waspurged with nitrogen gas followed by addition of dimethyl sulfide (1.251ml, 17.03 mmol). The reaction was warmed to room temperature. The crudematerial was purified by chromatography on a RediSep® pre-packed silicagel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with agradient of 0% to 80% EtOAc in hexane, to provide the title compound asan oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.35-0.59 (m, 3 H) 0.95 (dt, J=5.0,2.5 Hz, 2 H) 1.05-1.17 (m, 2 H) 1.43-1.69 (m, 1 H) 1.69-1.90 (m, 2 H)2.04-2.18 (m, 1 H) 2.17-2.32 (m, 2 H) 2.32-2.53 (m, 1 H) 2.58-2.94 (m, 5H) 2.94-3.11 (m, 4 H) 3.49 (s, 1 H) 3.53-3.72 (m, 2 H) 4.34-4.82 (m, 3H) 5.02-5.52 (m, 1 H) 7.01-7.15 (m, 2 H) 7.15-7.23 (m, 2 H), 9.89 (s,1H).

Step G: Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(((methylsulfonyl)oxy)methyl)-2-oxopiperidin-3-yl)acetate

A solution of((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-2-oxo-3-(2-oxoethyl)piperidin-3-yl)methylmethanesulfonate (Example 414, Step F, 1.0 g, 1.516 mmol) in MeOH wastreated with Oxone (0.932 g, 1.516 mmol) over a weekend. The reactionmixture was diluted with DCM and water. The organic extract was washedwith satd NaCl and dried over Na₂SO₄. The solution was filtered andconcentrated in vacuo to give the crude material as a white solid. Theproduct was purified by chromatography through a RediSep® pre-packedsilica gel column (Teledyne Isco, Lincoln, Nebr.) (12 g), eluting with agradient of 0% to 80% EtOAc in hexane, to provide the title compound asan oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.46-0.63 (m, 5 H) 1.01 (dd, J=7.7,2.3 Hz, 4H) 1.15-1.26 (m, 4 H) 1.79-1.98 (m, 2 H) 2.05 (dd, J=13.9, 3.1Hz, 1 H) 2.19 (dd, J=13.5, 5.1 Hz, 1 H) 2.28-2.40 (m, 2 H) 2.47-2.61 (m,1 H) 2.76-2.91 (m, 5 H) 2.91-3.02 (m, 6 H) 3.03-3.12 (m, 5 H) 3.12-3.26(m, 2 H) 3.42 (d, J=0.8 Hz, 2 H) 3.75 (s, 3 H) 4.05-4.28 (m, 1 H)4.50-4.62 (m, 2 H) 4.64-4.75 (m, 2 H) 4.81 (d, J=10.6 Hz, 1 H) 6.87-7.01(m, 3 H) 7.01-7.12 (m, 2 H) 7.13-7.21 (m, 3 H) 7.27 (d, J=7.6 Hz, 2 H).

Step H. (1S,3S,6S,7R)-Methyl7-(3-chlorophenyl)-6-(4-chlorophenyl)-5-((S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylateand (1R,3S,6S,7R)-methyl7-(3-chlorophenyl)-6-(4-chlorophenyl)-54S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylate

A solution of lithium bis(trimethylsilyl)amide, (1.0M in toluene, 290μl, 0.290 mmol) was added to a solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-3-(((methylsulfonyl)oxy)methyl)-2-oxopiperidin-3-yl)acetate(Example 414, Step G, 200 mg, 0.290 mmol) in THF at 0° C. over 10 mins.The reaction mixture was quencged with 1N HCl and extracted with DCM.The organic extract was washed with sat. aq. Na₂CO₃ solution and driedover Na₂SO₄. The solution was filtered and concentrated in vacuo to givethe crude material as a white glass. The product was purified bychromatography on a Redi-Sep pre-packed silica gel column (4 g), elutingwith a gradient of 0% to 80% EtOAc in hexane, to provide the titlecompounds as a mixture of diastereomers.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.40 (t, J=7.5 Hz, 3 H) 0.69-0.86(m, 3 H) 0.86-0.95 (m, 2 H) 1.01-1.14 (m, 3 H) 1.14-1.23 (m, 2 H) 1.25(dd, J=6.5, 4.3 Hz, 2 H) 1.43 (br. s., 3 H) 1.77 (dt, J=14.7, 7.4 Hz, 1H) 1.89-2.02 (m, 2 H) 2.14-2.26 (m, 2 H) 2.51 (t, J=11.7 Hz, 1 H)2.70-2.82 (m, 2 H) 2.84 (s, 3 H) 3.57-3.73 (m, 3 H) 4.67 (d, J=9.6 Hz, 1H) 6.74-6.88 (m, 2 H) 6.98 (d, J=8.0 Hz, 2 H) 7.06 (d, J=5.1 Hz, 2 H)7.17 (s, 2 H). Mass Spectrum (ESI) m/z=593.2 (M+H⁺).

Step I:(1R,3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-4S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylicacid and(1S,3S,6S,7R)-7-(3-Chlorophenyl)-6-(4-chlorophenyl)-5-4S)-1-(N-methylcyclopropanesulfonamido)butan-2-yl)-4-oxo-5-azaspiro[2.5]octane-1-carboxylicacid

The mixture of diastereomeric esters from Example 414, Step H wastreated with NaOH (3N in MeOH) overnight at room temperature. Thereaction mixture was acidified with 1N HCl (1N) and extracted into DCM.The organic extract was washed with satd NaCl and dried over Na2SO4. Theproduct was purified by chromatography on silica, eluting with agradient of 40% EtOAc in hexane, to provide the title compounds as amixture of diastereomers as a white glass.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.39 (t, J=7.5 Hz, 3 H) 0.81 (s, 1H) 0.89-1.02 (m, 2 H) 1.16-1.21 (m, 2 H) 1.21-1.30 (m, 1 H) 1.37 (dd,J=9.2, 5.7 Hz, 1 H) 1.47 (ddd, J=14.5, 7.6, 4.1 Hz, 1 H) 1.84 (ddd,J=14.5, 8.7, 7.3 Hz, 1 H) 1.95-2.05 (m, 1 H) 2.18 (dd, J=7.0, 5.7 Hz, 1H) 2.22-2.32 (m, 1 H) 2.66-2.85 (m, 3 H) 2.87 (s, 3 H) 3.11 (ddd,J=13.1, 10.4, 2.9 Hz, 1 H) 3.42 (s, 1 H) 4.05 (d, J=7.0 Hz, 1 H) 4.71(d, J=10.4 Hz, 1 H) 6.74 (dt, J=6.9, 1.6 Hz, 1 H) 6.82-6.95 (m, 3 H)6.98-7.11 (m, 2 H) 7.18 (d, J=8.4 Hz, 2 H); Mass Spectrum (ESI)m/z=579.1 (M+H⁺).

Example 4152-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-(((S)-1-oxobutan-2-yl)piperidin-3-yl)acetate

To a stirred solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 186, Step A, 360 mg, 0.752 mmol) in DCM (3.76 mL) was addedDess-Martin periodinane (383 mg, 0.903 mmol) and the reaction wasstirred at rt for 20 minutes. After this time the reaction was treatedwith Na₂S₂O₃ (30 mL, saturated aqueous solution) and DCM (40 mL) andstirred at rt for 10 minutes. The organic layer was separated and washedwith Na₂S₂O₃ (20 mL, saturated aqueous solution) and NaHCO₃ (20 mL,saturated aqueous solution), dried over MgSO₄, filtered and concentratedto give the title compound. MS (ESI) m/z=476.0 (M+1).

Step B. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-pent-1-en-3-yl)piperidin-3-yl)acetate

Tebbe reagent(Bis(cyclopentadienyl)-μ-chloro(dimethylaluminum)-μ-methylenetitanium,0.5 M solution in toluene, 1.7 mL, 0.85 mmol) was added dropwise over 5minutes to a stirred solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-1-oxobutan-2-yl)piperidin-3-yl)acetate(Example 415, Step A, 360 mg, 0.756 mmol) in toluene (4.7 mL) at 0° C.The reaction was stirred at 0° C. for 20 minutes and at rt for 30minutes. The reaction was recooled to 0° C. and an additional portion ofTebbe reagent (0.5 M solution in toluene, 1 mL, 0.5 mmol) was added. Thereaction was allowed to warm to rt for 20 minutes. The reaction wasrecooled to 0° C. and treated with sat. aq. NaHCO₃ solution (40 mL) andEtOAc (100 mL). The separated aqueous layer was extracted with EtOAc(2×60 mL) and the combined organic extracts were washed with brine (80ml), dried over MgSO₄, filtered and the filtrate was concentrated underreduced pressure. Column chromatography on silca gel (24 g, SiO₂,eluent: hexanes:EtOAc, 1:0 to 3:1, gradient elution) gave the titlecompound.

MS (ESI) m/z=474.0 (M+1).

Step C. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate

To a stirred solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxo-1-((S)-pent-1-en-3-yl)piperidin-3-yl)acetate(Example 415, Step B, 85 mg, 0.18 mmol) in THF (1 mL), t-butanol (1 mL)and water (1.5 mL) was added 4-methylmorpholine 4-oxide (63.0 mg, 0.54mmol) and OsO₄ (1.1 mg, 4.5 μmol). The reaction was stirred at rtovernight. The reaction was diluted with EtOAc (40 mL) and Na₂S₂O₃ (20mL, saturated aqueous solution). The separated aqueous layer wasextracted with EtOAc (20 mL) and the combined organic extracts werewashed with brine (20 mL), dried over MgSO₄, filtered and evaporated invacuo to give the title compound as a 5:1 mixture of diastereomers. MassSpectrum (ESI) m/e=508.0 (M+1).

Step D.2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

A solution of LiOH in water (1M, 502 μl, 0.502 mmol) was added to astirred solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 415, Step C; 85 mg, 0.167 mmol) in EtOH (1.67 mL). The reactionwas stirred at rt for 4 hours. After this time the reaction was quenchedwith sat. aq. NH₄Cl solution (20 mL) and treated with EtOAc (40 mL). Theseparated aqueous layer was extracted with EtOAc (2×20 mL) and thecombined organic extracts were dried over MgSO₄, filtered and thefiltrate was concentrated under reduced pressure. The product waspurified by reverse phase preparatory HPLC (Gemini™ Prep C₁₈ 10 μmcolumn; Phenomenex, Torrance, Calif., using 25 to 75% acetonitrile inwater with 0.1% TFA as eluent) to give one of the title compounds as theminor diastereomer, as the first eluting component.

¹H NMR (400 MHz, methanol-d₄) δ ppm 7.26 (4 H, br s), 7.11-7.17 (2 H,m), 7.07 (1 H, s), 6.93-6.98 (1 H, m), 4.75 (1 H, d, J=10.8 Hz), 3.78(1H, br s), 3.56-3.66 (2 H, m), 3.43 (1 H, td, J=11.3, 4.8 Hz),2.92-3.01 (2 H, m), 2.60 (1 H, d, J=13.7 Hz), 2.14-2.22 (2 H, m),1.94-2.05 (1 H, m), 1.72 (1 H, ddd, J=14.6, 7.6, 5.2 Hz), 1.38 (3H, s),0.51 (3 H, t, J=7.5 Hz); Mass Spectrum (ESI) m/z=494.0 (M+1).

Example 4162-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2R,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-1,2-dihydroxypentan-3-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

In the purification described in Example 415, Step D, the other of thetitle compounds was isolated as the major diastereomer, as the secondeluting component.

¹H NMR (500 MHz, methanol-d₄) δ ppm 7.18-7.25 (3 H, br s), 7.05-7.17 (4H, m), 6.88-6.98 (1 H, m), 4.83 (1 H, d, J=10.8 Hz), 3.96 (1 H, br s),3.59 (1 H, dd, J=11.2, 5.4 Hz), 3.51 (1 H, dd, J=11.2, 5.1 Hz),3.39-3.46 (1 H, m), 2.81-2.99 (2 H, m), 2.61 (1 H, d, J=13.7 Hz),2.12-2.27 (2 H, m), 1.84-1.96 (1 H, m), 1.60 (1 H, ddd, J=14.2, 7.8, 4.6Hz), 1.41 (3 H, m), 0.43 (3 H, t, J=7.3 Hz); Mass Spectrum (ESI)m/z=494.0 (M+1).

Example 4172-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A.(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one

Cyclopropylmagnesium bromide (0.5 M solution in THF, 2.0 mL, 1.013 mmol)was added dropwise via syringe over a period of 1 min to a stirredsolution of(S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal(Example 91, Step C, 150 mg, 0.338 mmol) in THF (1.7 mL) at rt. Thereaction mixture was stirred at rt for 20 minutes and then quenched withNH₄Cl (30 mL, saturated aqueous solution) and diluted with EtOAc (50mL). The organic layer was dried over MgSO₄, filtered and evaporated invacuo. Purification by column chromatography (24 g SiO₂, Hexanes:EtOAc,1:0 to 4:1) gave the title compound as a mixture of diastereomers.

MS (ESI) m/z=486.2 (M+1).

Step B.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a stirred solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one(Example 417, Step A; 60 mg, 0.123 mmol) in EtOAc (1 mL), acetonitrile(1 mL) and water (1.5 mL) was added ruthenium chloride hydrate (2.8 mg,0.012 mmol) and sodium meta-periodate (6.83 μl, 0.123 mmol) (portionwiseover 5 minutes). The reaction was stirred at rt for 20 minutes and thenpartitioned between EtOAc (60 mL) and water (20 mL). The separatedaqueous layer was extracted with EtOAc (2×20 mL) and the combinedorganic extracts were dried over MgSO₄, filtered and evaporated invacuo. Purification by column chromatography (12 g, SiO₂, hexanes/IPA,1:0 to 9:1) gave the title compound.

MS (ESI) m/z=502.1 (M+1).

Step C.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1S,2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid or2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((1R,2S)-1-cyclopropyl-1-hydroxybutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid

To a stirred solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-1-oxobutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 417, Step B, 33 mg, 0.066 mmol) in THF (657 μl) at −78° C.was added dropwise a solution of L-selectride (144 μl, 0.144 mmol). Thereaction mixture was stirred at −78° C. for 20 minutes and then it wasallowed to warm to rt for 30 minutes. After this time the reaction wasquenched with a solution of oxone (121 mg, 0.197 mmol) in water (3 mL).The reaction was diluted with EtOAc (30 mL) and the separated aqueouslayer was extracted with EtOAc (2×10 mL), dried over MgSO₄, filtered andevaporated in vacuo. Column chromatography (4 g, SiO₂, hexanes:IPA, 1:0to 4:1) gave the title compound as a single stereoisomer.

¹H NMR (400 MHz, CDCl₃) δ ppm 6.95-7.27 (7 H, m), 6.72 (1 H, dt, J=7.6,1.6 Hz), 4.58-4.70 (1 H, m), 3.07-3.34 (1 H, m), 2.80-2.93 (2 H, m),2.09-2.25 (4 H, m), 1.47 (3H, s), 0.28-1.47 (10 H, m); Mass Spectrum(ESI) m/z=504.0 (M+1).

Example 4182-((3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. (S)-2-(3-Chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-one and(R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-one

To a solution of KOH (57.1 g, 1.02 mol) in water (113 mL) was addedN-benzyl-N,N-diethylethanaminium chloride (1.289 g, 5.66 mmol). Asolution of 2-(3-chlorophenyl)-1-(4-chlorophenyl)ethanone (Example 1,Step A) (30 g, 113 mmol) in toluene (113 mL) was added followed by3-bromoprop-1-ene (10.77 mL, 124 mmol). The resulting biphase wasvigorously stirred at ambient temperature for twenty-one hours, thenseparated. The organic layer was washed with aqueous citric acidsolution followed by brine then dried over anhydrous MgSO₄ andconcentrated to afford the title compounds as a pale yellow oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.49-2.67 (m, 1 H) 2.86-3.04 (m, 1H) 4.57 (t, J=7.3 Hz, 1 H) 4.95-5.15 (m, 2 H) 5.75 (ddt, J=17.1, 10.2,6.9 Hz, 1H) 7.14-7.35 (m, 4 H) 7.36-7.47 (m, 2 H) 7.83-7.98 (m, 2 H).

Step B. (R)—N4R)-2-(3-Chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-ylidene)-2-methylpropane-2-sulfinamide

2-(3-Chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-one (Example 418, StepA, 48 g, 157 mmol), titanium(IV) ethoxide, technical grade (65.9 mL, 315mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (Combi-Blocks, SanDiego, Calif., 33.1 g, 267 mmol) were dissolved in 400 mL of THF. Themixture was heated with stirring under reflux for eighteen hours. Thereaction was cooled and poured into brine. The resulting white solid wasremoved by filtration, rinsing with ethyl acetate. Ethyl acetate wasadded to the biphasic filtrate and the layers separated. The organiclayer was washed with brine, then dried with anhydrous magnesium sulfateand concentrated. The crude product was purified by threechromatographies (330 g RediSep® pre-packed silica gel column (TeledyneIsco, Lincoln, Nebr.), eluting with hexane:ethyl acetate, 95:5 to 85:5)to afford the title compound eluting second on silica gel TLC inhexane/ethyl acetate, the diastereomer (R)—N—((S)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-en-1-ylidene)-2-methylpropane-2-sulfinamideeluting third on silica gel TLC in hexane/ethyl acetate, and somestarting ketone eluting first on silica gel TLC in hexane/ethyl acetate.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (s, 9 H) 2.58-2.75 (m, 1 H)2.85-3.02 (m, 1 H) 3.80-4.12 (m, 1 H) 5.01-5.16 (m, 2 H) 5.76 (ddt,J=17.0, 10.2, 6.8 Hz, 1 H) 6.94-7.11 (m, 2 H) 7.11-7.20 (m, 1 H)7.20-7.38 (m, 5 H).

Step C.(R)—N-((2S,3R)-3-(3-Chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-yl)-2-methylpropane-2-sulfinamide

A solution of(R)—N—((R)-2-(3-chlorophenyl)-1-(4-chlorophenyl)pent-4-enylidene)-2-methylpropane-2-sulfinamide(Example 418, Step B, 9.97 g, 24.41 mmol) in THF (98 ml) was cooled to−78° C. Methyllithium (1.6M in ether, 16.78 ml, 26.9 mmol) was addedover a period of six min. The reaction was removed from the cold bathand diluted with 500 mL ether and quenched with 150 mL of saturatedaqueous ammonium chloride solution. The organic layer was separated andwashed with brine, then dried with anhydrous magnesium sulfate andconcentrated to afford a colorless oil. The crude material was adsorbedonto a plug of silica gel and purified by chromatography through (3×80g) RediSep® pre-packed silica gel column (Teledyne Isco, Lincoln,Nebr.), eluting with 30% ethyl acetate in hexane. Fractions containingthe desired product, eluting as the bottom spot on silica gel TLC inhexane/ethyl acetate, were combined and concentrated under reducedpressure to provide the title compound as a glass.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (s, 9 H) 1.80 (s, 3 H) 2.23 (td,J=13.3, 7.5 Hz, 1 H) 2.62-2.76 (m, 1H) 3.30 (d, J=3.3 Hz, 1H) 4.81 (d,J=10.4 Hz, 1 H) 4.85-4.97 (m, 1 H) 5.10 (s, 1 H) 5.31-5.52 (m, 1 H) 6.79(d, J=7.2 Hz, 1 H) 6.97 (s, 1 H) 7.05-7.23 (m, 4 H) 7.28 (d, J=8.8 Hz, 2H).

Step D. (2S,3R)-3-(3-Chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-amine

A solution of(R)—N-(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-yl)-2-methylpropane-2-sulfinamide(Example 418, Step C, 5.96 g, 14.04 mmol) in THF (56.2 ml) was treatedwith. hydrochloric acid in water (36-38% wt, 6.40 ml, 211 mmol) forthree hours. The reaction was diluted with 300 mL ether and the acidicaqueous layer made alkaline with sat. aq. NaHCO₃ solution. The organiclayer was washed with sat. aq. NaHCO₃ solution, dried over MgSO₄ andconcentrated to provide the title compound as a colorless glass.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (s, 3 H) 1.46 (br s, 2 H)2.09-2.25 (m, 1 H) 2.41 (ddd, J=13.6, 12.7, 6.9 Hz, 1 H) 2.99 (dd,J=11.9, 3.3 Hz, 1 H) 4.71-4.88 (m, 2 H) 5.39 (ddt, J=17.0, 10.2, 6.8 Hz,1 H) 6.99-7.13 (m, 1 H) 7.17-7.31 (m, 3 H) 7.31-7.38 (m, 2 H) 7.38-7.48(m, 2 H).

Step E.(2S,3R)-3-(3-Chlorophenyl)-2-(4-chlorophenyl)-N-isopropylhex-5-en-2-amine

A mixture of(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)hex-5-en-2-amine (Example418, Step D) (270 mg, 0.843 mmol), acetic acid (0.243 mL, 4.22 mmol),acetone (3.10 mL, 42.2 mmol) and sodium cyanoborohydride (0.442 mL, 8.43mmol) in methanol (4 mL) was heated to 65° C. overnight. After sixteenhours, an additional ten equivalents of sodium cyanoborohydride wereadded and heating continued for another five hours then equilibrated toroom temperature and concentrated under reduced pressure. Theconcentrate was partitioned between aqueous sodium hydroxide solutionand ethyl acetate. The aqueous layer was extracted again with ethylacetate. The combined organic layers were washed with brine, dried overMgSO₄ and concentrated to afford a yellow oil. The crude product wasadsorbed onto silica and purified by chromatography (24 g RediSep®pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) elutingwith 30 to 100% ethyl acetate gradient in hexane. Fractions containingproduct were combined and concentrated to afford the title compound as acolorless glass.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.95 (d, J=6.1 Hz, 3 H) 1.09 (d,J=6.1 Hz, 3 H) 1.38 (br s, 1 H) 1.51 (s, 3 H) 2.32-2.50 (m, 1 H)2.59-2.81 (m, 3 H) 4.78-4.86 (m, 1 H) 4.86-4.98 (m, 1 H) 5.46 (ddt,J=17, 10.2, 6.7 Hz, 1 H) 6.78 (d, J=7.6 Hz, 1 H) 6.96 (t, J=1.8 Hz, 1 H)7.03-7.11 (m, 1 H) 7.11-7.21 (m, 3 H) 7.21-7.29 (m, 2 H).

Step F.(4R,5S)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexan-1-ol

To a solution of(2S,3R)-3-(3-chlorophenyl)-2-(4-chlorophenyl)-N-isopropylhex-5-en-2-amine(Example 418, Step E, 160 mg, 0.442 mmol) in THF (4 mL) cooled by anice-water bath was added borane-tetrahydrofuran complex, (1.0M in THF,2.21 mL, 2.21 mmol). After 90 minutes, an additional 5 equivalents ofborane-THF were added and the cold bath removed. After 30 minutes thereaction was cooled in an ice-water bath and quenched by addition of 0.5mL water followed by 4N aqueous sodium hydroxide (1.1 mL, 4.42 mmol) andaqueous hydrogen peroxide solution, (30% (w/w), 0.45 mL, 4.42 mmol). Thebiphasic mixture was stirred rapidly at 0-5° C. for 15 minutes thenpartitioned between water and ethyl acetate. The aqueous layer wasextracted again with ethyl acetate. The combined organic layers werewashed with brine then dried with anhydrous magnesium sulfate andconcentrated to afford a colorless oil. The product was isolated bychromatography on silica (24 g RediSep® pre-packed silica gel column(Teledyne Isco, Lincoln, Nebr.)) eluting with 50 to 100% ethyl acetategradient in hexane to afford the title compound as a colorless oil.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.91 (d, J=6.3 Hz, 3 H) 1.06 (d,J=6.3 Hz, 3 H) 1.13-1.37 (m, 2 H) 1.48 (s, 3 H) 1.56-1.86 (m, 3 H)1.89-2.04 (m, 1 H) 2.50-2.75 (m, 2 H) 3.52 (t, J=6.4 Hz, 2 H) 6.76 (d,J=7.6 Hz, 1 H) 6.89-6.98 (m, 1 H) 7.01-7.08 (m, 1 H) 7.08-7.17 (m, 3 H)7.17-7.26 (m, 2 H).

Step G.(4R,5S)-4-(3-Chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexanoicacid

To a solution of(4R,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexan-1-ol(Example 418, Step F, 185 mg, 0.486 mmol) in wet acetonitrile (0.75%water v/v) (3 mL) at ambient temperature was added over three minutes asolution of periodic acid (0.44M in acetonitrile(0.75% water v/v), 2.76mL, 1.216 mmol) with chromium trioxide (2.43 mg, 0.024 mmol). Thereaction was stirred for fifteen minutes. To the reaction was added asolution of 0.6 g disodium hydrogen phosphate in 10 mL water. Theaqueous mixture was extracted with toluene. The organic layer was washedwith water/brine then with a solution of 0.2 g sodium hydrogen sulfitein 5 mL water. The organic layer was then dried with anhydrous magnesiumsulfate and concentrated to afford a peach-colored foamy solid. Theproduct was isolated by chromatography on silica (24 g RediSep®pre-packed silica gel column (Teledyne Isco, Lincoln, Nebr.)) elutingwith 50-100% ethyl acetate gradient in hexane to afford the titlecompound as a colorless foam.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.7 Hz, 4 H) 1.32 (d,J=6.7 Hz, 4 H) 1.43 (s, 3 H) 1.76-1.88 (m, 1 H) 2.22-2.38 (m, 1 H)2.55-2.67 (m, 2 H) 2.79 (quin, J=6.65 Hz, 1 H) 3.11 (dd, J=13.1, 2.4 Hz,1 H) 6.21 (d, J=7.8 Hz, 1 H) 6.49 (s, 1 H) 6.91 (dd, J=7.9, 7.9 Hz, 1 H)6.96-7.17 (m, 3 H) 7.23 (d, J=8.2 Hz, 2 H).

Step H.(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one

Oxalyl chloride (˜0.38 M in benzene, 0.617 mL, 0.234 mmol) was added toa room temperature solution of(4R,5S)-4-(3-chlorophenyl)-5-(4-chlorophenyl)-5-(isopropylamino)hexanoicacid (Example 418, Step G, 84 mg, 0.213 mmol) in benzene (3 mL) followedby a drop of DMF. The reaction solution was stirred at room temperaturefor 25 minutes then heated to 80° C. After 3.5 hours the reaction wasremoved from heat and saturated aqueous sodium bicarbonate solution wasadded. The organic phase was diluted with ethyl acetate. The aqueouslayer was extracted again with ethyl acetate. The combined organiclayers were washed with brine, then dried with anhydrous magnesiumsulfate and concentrated to afford a red-orange oil. The product wasisolated by chromatography on silica (12 g RediSep Rf cartridge) elutingwith 20-40% ethyl acetate gradient in hexane to afford the titlecompound as a pale yellow film. [α]_(D)=+89.33° (T=24.0° C.; c=1, CHCl₃)

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.25 (d, J=6.7 Hz, 3 H) 1.41 (d,J=6.7 Hz, 3 H) 1.52 (s, 3 H) 1.84-1.98 (m, 1 H) 2.30-2.50 (m, 1 H)2.64-2.75 (m, 2 H) 2.88 (quin, J=6.7 Hz, 1 H) 3.20 (dd, J=13.2, 2.5 Hz,1 H) 6.31 (d, J=7.6 Hz, 1 H) 6.58 (dd, J=1.8, 1.8 Hz, 1 H) 7.00 (dd,J=7.9, 7.9 Hz, 1 H) 7.05-7.27 (m, 3 H) 7.27-7.42 (m, 2 H); Mass Spectrum(ESI) m/z=376.1 [M+H]⁺.

Step I.(3R,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-oneand(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one

sec-Butyllithium (0.8N in cyclohexane, 0.274 mL, 0.219 mmol) was addedover a period of one minute to a degassed (Argon bubbled throughsolution for 10 minutes at RT) solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one(Example 418, Step H, 75 mg, 0.199 mmol) in THF (6 mL) cooled by anacetone-dry ice bath. The cold bath was removed and the reactionequilibrated to room temperature over fifteen minutes. The reaction wasstirred at room temperature for 30 minutes. Allyl bromide (1M in THF,0.219 mL, 0.219 mmol) was added over one minute at room temperature.After two hours the reaction was quenched by addition of saturatedaqueous ammonium chloride solution. The organic layer was diluted withethyl acetate and separated. The aqueous layer was extracted again withethyl acetate. The combined organic layers were then dried withanhydrous magnesium sulfate and concentrated to afford a faintly orangeglass. The diastereomeric products were isolated by chromatography onsilica gel (12 g RediSep® pre-packed silica gel column (Teledyne Isco,Lincoln, Nebr.)) eluting with 20 to 80% ethyl acetate gradient in hexaneto afford 25 mg of(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-oneas the product eluting first on silica gel TLC plate (R_(f)=0.52 in 3:1hexane:ethyl acetate eluent) and 25 mg of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-oneas the product eluting second on silica gel TLC plate (R_(f)=0.28 in 3:1hexane:ethyl acetate eluent).

Diastereomer 1:(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.17 (d, J=6.7 Hz, 3 H) 1.31 (d,J=6.7 Hz, 3 H) 1.41 (s, 3 H) 1.84 (ddd, J=13.3, 5.8, 2.5 Hz, 1 H)2.03-2.21 (m, 1 H) 2.41-2.54 (m, 1 H) 2.54-2.69 (m, 2 H) 2.78 (quin,J=6.7 Hz, 1 H) 3.18 (dd, J=13.4, 2.3 Hz, 1 H) 4.92-5.18 (m, 2 H)5.56-5.84 (m, 1 H) 6.20 (d, J=7.8 Hz, 1 H) 6.50 (s, 1 H) 6.90 (dd,J=7.8, 7.8 Hz, 1 H) 7.00-7.08 (m, 1 H) 7.08-7.37 (m, 4 H); MS (ESI)416.2 [M+H]⁺

Diastereomer 2:(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.7 Hz, 3 H) 1.35 (d,J=6.7 Hz, 3 H) 1.43 (s, 3 H) 1.75-1.80 (m, 1 H) 2.25-2.48 (m, 2 H)2.56-2.68 (m, 1 H) 2.69-2.89 (m, 2 H) 3.23 (dd, J=13.6, 2.6 Hz, 1 H)4.91-5.06 (m, 2 H) 5.76 (dddd, J=17.6, 9.5, 8.3, 5.9 Hz, 1 H) 6.25 (d,J=7.8 Hz, 1 H) 6.51 (dd, J=1.8, 1.8 Hz, 1 H) 6.87-6.97 (m, 1 H)6.97-7.12 (m, 3 H) 7.19-7.32 (m, 2 H); MS (ESI) 416.2 [M+H]⁺

Step J.2-((3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3R,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one(Example 418, Step I, diastereomer 1) by a procedure similar to the onedescribed in Example 1, Step H.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.16 (d, J=6.7 Hz, 3 H) 1.33 (d,J=6.7 Hz, 3 H) 1.46 (s, 3 H) 1.87-2.01 (m, 1 H) 2.27 (q, J=13 Hz, 1 H)2.62 (dd, J=15.8, 3.2 Hz, 1 H) 2.76-3.06 (m, 3 H) 3.24 (dd, J=13.3, 2.2Hz, 1 H) 6.19 (d, J=7.8 Hz, 1 H) 6.40-6.52 (m, 1 H) 6.92 (dd, J=7.9, 7.9Hz, 1 H) 7.07 (ddd, J=8.0, 2, 0.98 Hz, 1 H) 7.10-7.40 (m, 4 H); MS (ESI)432.0 [M−H]⁻.

Example 4192-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methyl-2-oxopiperidin-3-yl)aceticacid

The title compound was prepared from(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-isopropyl-6-methylpiperidin-2-one(Example 418, Step I, diastereomer 2) by a procedure similar to the onedescribed in Example 1, Step H.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J=6.7 Hz, 3 H) 1.34 (d,J=6.7 Hz, 3 H) 1.47 (s, 3 H) 1.75 (d, J=13.9 Hz, 1 H) 2.46-2.65 (m, 2 H)2.92 (quin, J=6.7 Hz, 1 H) 2.99-3.22 (m, 3 H) 6.26 (d, J=7.8 Hz, 1 H)6.51 (s, 1 H) 6.94 (dd, J=7.9, 7.9 Hz, 1 H) 6.98-7.12 (m, 3 H) 7.28 (d,J=8.6 Hz, 2 H); Mass Spectrum (ESI) m/z=432.0 [M−H]⁻.

Example 420(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one

Step A:(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)piperidin-2-one

This compound was made according to the procedure of Example 174, StepA, utilizing propanesulfatam (J. Org. Chem., 1963, 28 3537, 4.63 g, 38.2mmol) and(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)piperidin-2-one(Example 185, Step B, 6.0 g, 15.29 mmol). The title compound wascrystallized from ethyl acetate and hexanes.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.24 (d, J=8.1 Hz, 2H), 7.10-7.20(m, 2H), 6.99-7.09 (m, 3H), 6.86 (d, J=7.1 Hz, 1H), 4.74 (d, J=9.3 Hz,1H), 3.36-3.46 (m, 1H), 2.96-3.33 (m, 5H), 2.93 (ddd, J=3.2, 9.3, 12 Hz,1H), 2.63-2.71 (m, 2H), 2.32-2.50 (m, 2H), 2.12-2.26 (m, 1H), 1.97-2.04(m, 1H), 1.91 (quind, J=7.5, 14.8 Hz, 1H), 1.44-1.61 (m, 1H), 0.53 (t,J=7.5 Hz, 3H). Mass Spectrum (ESI) m/z=495.1 (M+1).

Step B. 2-(iodomethyl)-6-methoxypyridine

To a 0° C. solution of iodine (1.094 g, 4.31 mmol) and imidazole (0.294g, 4.31 mmol) in dichloromethane (10.27 ml) was added portionwisetriphenylphosphine (1.131 g, 4.31 mmol). After 20 min of stirring,(6-methoxypyridin-2-yl)methanol (Adesis, New Castle, Del., 0.5 g, 3.59mmol) was added to the solution. The reaction was allowed to stir for 1h at 0° C., quenched with water (50 mL) and extracted with Et₂O. Thecombined organics were dried over MgSO₄, and concentrated in vacuo.Silica gel chromatography (gradient elution 1 to 5% Et₂O in pentane)afforded 2-(iodomethyl)-6-methoxypyridine. ¹H NMR (500 MHz,CHLOROFORM-d) δ ppm 7.49 (dd, J=7.3, 8.3 Hz, 1H), 6.96 (d, J=7.1 Hz,1H), 6.61 (d, J=8.1 Hz, 1H), 4.44 (s, 2H), 3.94 (s, 3H). Mass Spectrum(ESI) m/z=249.9 (M+1).

Step C.(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one

To a solution of(5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)piperidin-2-one(Example 420, Step A, 0.7 g, 1.413 mmol) in THF (5.65 ml) at −78° C. wasadded dropwise sec-butyllithium, (1.4 M in cyclohexane, 1.06 ml, 1.483mmol). The reaction was warmed to −10° C. After about 5 minutes, thereaction was returned to a −78° C. bath. A solution of2-(iodomethyl)-6-methoxypyridine (Example 420, Step B, 0.387 g, 1.554mmol) in THF (1 mL) was added dropwise to the cooled reaction mixture.The reaction was allowed to warm to room temparature and stirred for 1h. The reaction contents were poured into saturated sodium bicarbonateand the aqueous layer was extracted with dichloromethane (3×50 mL). Thecombined organics were dried with sodium sulfate and concentrated invacuo. Silica gel chromatography (step gradient elution 5 to 50% diethylether in dichloromethane) afforded the title compound as the more polardiastereomer.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.50 (t, J=7.8 Hz, 1H), 7.25 (d,J=8.6 Hz, 2H), 7.09-7.18 (m, 3H), 7.03 (d, J=8.3 Hz, 2H), 6.92-6.99 (m,1H), 6.82 (d, J=7.3 Hz, 1H), 6.58 (d, J=8.1 Hz, 1H), 4.87 (d, J=7.6 Hz,1H), 3.80 (s, 3H), 3.36-3.46 (m, 2H), 2.99-3.32 (m, 7H), 2.26-2.50 (m,2H), 2.03-2.15 (m, 1H), 1.90-2.03 (m, 2H), 1.43-1.73 (m, 2H), 0.56 (t,J=7.6 Hz, 3H). Mass Spectrum (ESI) m/z=616.1 (M+1).

Example 421(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one

From the purification described in Example 420, Step C,(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-onewas isolated as the less polar diastereomer.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.46 (t, J=7.8 Hz, 1H), 7.22 (d,J=8.31 Hz, 2H), 7.10-7.17 (m, 1H), 7.05-7.10 (m, 1H), 6.98-7.03 (m, 3H),6.79 (d, J=7.1 Hz, 1H), 6.75 (d, J=7.3 Hz, 1H), 6.54 (d, J=8.3 Hz, 1H),4.68 (d, J=10.3 Hz, 1H), 3.91 (s, 3H), 3.72 (dd, J=3.8, 14.1 Hz, 1H),3.30 (t, J=6.7 Hz, 2H), 3.09-3.26 (m, 4H), 3.00-3.08 (m, J=14.4 Hz, 1H),2.95 (ddd, J=3.2, 10.2, 13.0 Hz, 2H), 2.68 (dd, J=10.0, 14.2 Hz, 1H),2.30-2.53 (m, 2H), 2.10 (q, J=12.9 Hz, 1H), 1.85-2.01 (m, 2H), 1.57-1.63(m, J=2.2, 7.1 Hz, 1H), 0.53 (t, J=7.6 Hz, 3H). Mass Spectrum (ESI)m/z=616.1 (M+1).

Example 422(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-one

To the product of Example 420, Step C (0.05 g, 0.081 mmol) in chloroform(1.622 ml) was added iodotrimethylsilane (0.046 ml, 0.324 mmol). Thereaction was warmed to 50° C. After 4 hours, the reaction was quenchedwith saturated bicarbonate (10 mL) and extracted with dichloromethane(2×15 mL) and 5% MeOH in CH₂Cl₂ (1×15 mL). The combined organics weredried with sodium sulfate and concentrated in vacuo. Silica gelchromatography (0.5 to 7.5% MeOH in dichloromethane) afforded the titlecompound.

¹H NMR (500 MHz, CHLOROFORM-d) δ 7.36 (dd, J=6.7, 9.2 Hz, 2H), 7.28 (brs, 1H), 7.26 (s, 1H), 7.12-7.20 (m, J=7.1 Hz, 3H), 7.05 (d, J=7.1 Hz,1H), 7.00 (d, J=8.3 Hz, 2H), 6.46 (d, J=9.1 Hz, 1H), 6.03 (d, J=6.6 Hz,1H), 5.01 (d, J=4.9 Hz, 1H), 3.64-4.03 (m, 1H), 3.40-3.57 (m, 1H),2.85-3.34 (m, 8H), 2.74 (quin, J=6.4 Hz, 1H), 2.25-2.50 (m, 2H),1.91-2.17 (m, J=6.8 Hz, 3H), 1.39-1.55 (m, 1H), 0.61 (t, J=7.5 Hz, 3H).Mass Spectrum (ESI) m/z=602.2 (M+1).

Example 423(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-one

Following the procedure of Example 422 using the product of Example 421,(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)piperidin-2-onewas obtained.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.22 (dd, J=6.6, 9.3 Hz, 1H), 7.16(d, J=8.3 Hz, 2H), 7.07-7.11 (m, 1H), 7.00-7.06 (m, 1H), 6.95 (s, 1H),6.90 (d, J=8.07 Hz, 2H), 6.70 (d, J=7.6 Hz, 1H), 6.36 (d, J=9.1 Hz, 1H),5.87 (d, J=6.6 Hz, 1H), 4.65 (d, J=10.5 Hz, 1H), 3.29 (td, J=6.7, 9.60Hz, 1H), 3.18 (td, J=6.7, 9.6 Hz, 1H), 3.11 (t, J=7.5 Hz, 2H), 2.87-3.04(m, 3H), 2.76-2.86 (m, 1H), 2.71 (dd, J=2.7, 14.4 Hz, 1H), 2.32 (quin,J=7.0 Hz, 2H), 2.17 (q, J=13 Hz, 1H), 1.84-1.99 (m, 2H), 1.37-1.58 (m,2H), 0.43 (t, J=7.6 Hz, 3H).

Example 424(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpiperidin-2-one

sec-Butyllithium (1.4 M in cyclohexane, 0.59 ml, 0.824 mmol) was addedto a solution of(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)piperidin-2-one(Example 420, Step C, 0.484 g, 0.785 mmol) in THF (3.92 ml) at −78° C.After 15 minutes iodomethane (0.098 ml, 1.57 mmol) was added and thereaction was allowed to warm to room temperature. The reaction contentswere poured into saturated sodium bicarbonate (20 mL) and extracted withdichloromethane (3×30 mL). The combined organics were dried with sodiumsulfate and concentrated in vacuo. Silica gel chromatography (10% stepgradient elution 30 to 90% EtOAc in hexanes) afforded the title compoundas the first eluting diastereomer.

¹H NMR (500 MHz, CHLOROFORM-d) δ 7.48 (t, J=7.6 Hz, 1H), 7.21 (d, J=8.1Hz, 2H), 6.92-7.15 (m, 5H), 6.88 (d, J=7.1 Hz, 1H), 6.74 (d, J=7.6 Hz,1H), 6.57 (d, J=8.3 Hz, 1H), 4.64 (d, J=10.5 Hz, 1H), 3.04-3.25 (m, 7H),2.98 (d, J=14.7 Hz, 2H), 2.69 (t, J=13.8 Hz, 1H), 2.21-2.44 (m, 2H),1.89 (td, J=7.4, 14.6 Hz, 1H), 1.75 (dd, J=2.8, 13.6 Hz, 1H), 0.50 (t,J=7.6 Hz, 3H). Mass Spectrum (ESI) m/z=630.2 (M+1).

Example 425(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-methoxypyridin-2-yl)methyl)-3-methylpiperidin-2-one

The title compound is the second eluting diastereomer from thepurification described in Example 424.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.53 (t, J=7.7 Hz, 1H), 7.19 (d,J=8.1 Hz, 2H), 7.03-7.13 (m, 2H), 6.87-7.03 (m, 3H), 6.84 (d, J=7.3 Hz,1H), 6.76 (d, J=7.3 Hz, 1H), 6.62 (d, J=8.3 Hz, 1H), 4.72 (d, J=10.8 Hz,1H), 3.86-4.00 (m, 1H), 3.69 (s, 3H), 3.43 (d, J=12.7 Hz, 1H), 3.26-3.39(m, 2H), 3.14-3.26 (m, 3H), 2.96-3.05 (m, 2H), 2.91 (br. s., 1H),2.31-2.51 (m, 2H), 2.14-2.23 (m, 1H), 2.02-2.12 (m, 1H), 1.95 (quind,J=7.6, 14.8 Hz, 1H), 1.39-1.64 (m, 2H), 1.29 (s, 3H), 0.51 (t, J=7.6 Hz,3H). Mass Spectrum (ESI) m/z=630.2 (M+1).

Example 426(3S,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-one

Following the procedure of Example 422 using the product of Example 424,(3S,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-onewas obtained.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.33 (dd, J=6.7, 9.2 Hz, 1H), 7.23(d, J=8.1 Hz, 2H), 7.08-7.19 (m, 2H), 6.87-7.05 (m, 4H), 6.81 (d, J=7.6Hz, 1H), 6.49 (d, J=9.1 Hz, 1H), 5.95 (d, J=6.6 Hz, 1H), 4.74 (d, J=10.3Hz, 1H), 3.75-4.14 (m, 1H), 3.30-3.42 (m, 1H), 3.10-3.28 (m, 4H),2.68-3.09 (m, J=4.2 Hz, 4H), 2.26-2.50 (m, 3H), 1.89-2.06 (m, 1H),1.53-1.70 (m, J=3.2, 13.2 Hz, 2H), 1.49 (s, 3H), 0.52 (t, J=7.5 Hz, 3H).Mass Spectrum (ESI) m/z=616.1 (M+1).

Example 427(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-one

Following the procedure of Example 422 using the product of Example 425,(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-4S)-1-(1,1-dioxidoisothiazolidin-2-yl)butan-2-yl)-3-((6-hydroxypyridin-2-yl)methyl)-3-methylpiperidin-2-onewas obtained.

¹H NMR (500 MHz, CHLOROFORM-d) δ ppm 7.36-7.44 (m, 1H), 7.10-7.23 (m,2H), 6.77-7.07 (m, 5H), 6.66 (d, J=7.8 Hz, 1H), 6.48 (d, J=9.1 Hz, 1H),6.11 (d, J=6.6 Hz, 1H), 4.74 (d, J=10.5 Hz, 1H), 3.93 (dd, J=9.8, 13.9Hz, 1H), 3.29 (t, J=6.6 Hz, 2H), 3.20 (dt, J=0.9, 7.5 Hz, 2H), 3.15 (d,J=13.9 Hz, 1H), 2.75-2.99 (m, 4H), 2.32-2.48 (m, 1H), 2.24 (t, J=13.8Hz, 1H), 1.98-2.10 (m, 1H), 1.88-1.96 (m, J=2.9 Hz, 1H), 1.44-1.59 (m,1H), 1.39 (s, 3H), 0.48 (t, J=7.6 Hz, 3H). Mass Spectrum (ESI) m/z=616.1(M+1).

Example 428(3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-(3-hydroxy-2-oxopropyl)-3-methylpiperidin-2-one

Oxalyl chloride (0.063 ml, 0.715 mmol) was added to a solution of2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-cyclopropyl-2-(ethylsulfonyl)ethyl)-3-methyl-2-oxopiperidin-3-yl)aceticacid (Example 349, 0.316 g, 0.572 mmol) in dichloromethane (1.9 ml). Thereaction was stirred for 3 h at room temperature. The solvents wereremoved in vacuo. To the solids was added tris(trimethylsiloxy)ethylene(0.42 ml, 1.26 mmol) and the reaction was stirred at 90° C. After 2 h,the reaction was cooled, charged with THF (1 mL) and HCl (1.4 M, 0.982ml, 1.375 mmol), and brought to reflux for 30 min. After cooling, thereaction was poured into water (20 mL) and extracted withdichloromethane (3×20 mL). The combined organics were dried over sodiumsulfate and concentrated in vacuo. Silica gel chromatography (stepgradient elution 1 to 5% 2 M ammonia in MeOH in dichloromethane)afforded the title compound.

¹H NMR (500 MHz, CHLOROFORM-d) δ 7.11-7.30 (m, 3H), 6.96-7.10 (m, 3H),6.89 (s, 1H), 6.70-6.85 (m, 1H), 4.82 (d, J=10.8 Hz, 1H), 4.13-4.45 (m,J=1.7 Hz, 3H), 3.15 (ddd, J=2.9, 10.6, 13.6 Hz, 1H), 2.74-3.10 (m, 6H),2.60 (br s, 1H), 2.28 (t, J=13.8 Hz, 1H), 1.96 (dd, J=3.1, 13.8 Hz, 1H),1.77 (br s, 1H), 1.27-1.42 (m, 6H), 0.10-0.41 (m, 2H), −0.33 (br s, 1H),−1.01 (br s, 1H). Mass Spectrum (ESI) m/z=566.2 (M+1).

Example 4292-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Step A. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate

Sodium periodate (21.03 g, 98 mmol) was added slowly to a solutioncontaining ruthenium(III) chloride hydrate (0.277 g, 1.229 mmol) and(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methylpiperidin-2-one(4.6 g, 12.29 mmol; Example 71, step D) in acetonitrile (35.1 mL), ethylacetate (35.1 mL) and water (52.7 mL) while maintaining a temperaturebelow 20° C. The resulting mixture was then stirred for 2 h at roomtemperature. Next, the reaction was filtered and concentrated, and theresulting residue was further processed by dissolving in ethyl acetate.The organics were washed with water and brine, dried over MgSO₄,filtered and concentrated. Next, the residue was dissolved in a smallamount of a mixture of ether and methanol (1:1) and a 2M solution of(trimethylsilyl)diazomethane in diethyl ether (12.29 ml, 24.58 mmol) wasadded. This solution was then allowed to stir at ambient temperatureovernight. The solution was concentrated and the resulting residue waspurified on silica gel (eluent: hexane/ethyl acetate 0 to 100%, gradientelution) to give the title compound. Mass Spectrum (ESI) m/z=406 (M+1).

Step B. Methyl2-((3R,5R,6S)-1-amino-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate

A suspension of 60% sodium hydride in mineral oil (0.953 g, 23.82 mmol)was added to solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 429, step A, 4.84 g, 11.9 mmol) in DMF (25 mL). The resultingmixture was stirred for 15 min at 23° C.O-(2,4-dinitrophenyl)hydroxylamine (4.74 g, 23.82 mmol) was added atroom temperature. The solution was stirred for 1 h at room temperaturethen quenched with MeOH (1 mL). Excess solvent was removed under reducedpressure and the residue was purified by chromatography on silica(eluent: 0 to 5% MeOH in DCM; stepwise gradient) to give the titlecompound. Mass Spectrum (ESI) m/z=421 (M+1), 443 (M+23).

Step C. Methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxopiperidin-3-yl)acetate

Ethyl iodide (67.1 μL, 0.831 mmol) was added to a solution of methyl2-((3R,5R,6S)-1-amino-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 429, step B, 35 mg, 0.083 mmol) and DIEA (145 μL, 0.831 mmol)in DMF. The resulting mixture was stirred at 80° C. for 12 h. Themixture was concentrated and purified by reversed phase HPLC (Sunfire™Prep C₁₈ OBD 10 um column; Waters, Milford, Mass.; 40-90%water/acetonitrile gradient with 0.1% TFA). Desired fractions werepooled and concentrated to give the title compound.

Mass Spectrum (ESI) m/z=477 (M+1).

Step D.2-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxopiperidin-3-yl)aceticacid

A solution of methyl2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-(diethylamino)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 429, step C) in water/methanol (1:1) was treated with lithiumhydroxide (1N, 5 eq) at room temperature for 15 h. The mixture wasconcentrated and purified by reversed phase HPLC (Sunfire™ Prep C₁₈ OBD10 um column; Waters, Milford, Mass.; 40-90% water/acetonitrile gradientwith 0.1% TFA). Desired fractions were then pooled and concentrated togive the title compound.

¹H NMR (500 MHz, Methanol-d₄) δ ppm 0.222 (t, J=7Hz, 3 H) 1.179 (t,J=7Hz, 3 H) 1.389 (s, 3 H) 2.143 (dd, J=14, 3.5 Hz, 1H) 2.200 (t, J=13.5Hz, 1H) 2.570 (d, J=13.5 Hz, 1 H) 2.713 (m, 1 H) 2.967 (d, J=13.5 Hz, 1H) 3.116 (m, 1 H) 3.251 (m, 1 H) 3.519 (ddd, J=13, 11, 3.5 Hz, 1 H)4.598 (d, J=11 Hz, 1H) 6.972 (d, J=7Hz, 1 H) 7.070 (m, 1 H) 7.099-7.16(m, 2 H) 7.229 (m, 4 H); Mass Spectrum (ESI) m/z=463 (M+1), 485 (M+23).

Example 4302-((3R,5R,6S)-5-(3-Chlorophenyl)-6-(4-chlorophenyl)-1-(dimethylamino)-3-methyl-2-oxopiperidin-3-yl)aceticacid

Methyl2-((3R,5R,6S)-1-amino-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl)acetate(Example 429 step C) was treated by a procedure similar to the onedescribed in Example 429, using methyl iodide instead of ethyl iodide inStep C.

¹H NMR (500 MHz, Methanol-d₄) δ ppm 1.356 (s, 3 H) 2.088 (dd, J=14, 3.5Hz, 1H) 2.166 (t, J=13.5 Hz, 1H) 2.599 (br s, 6H) 2.601 (d, J=13.5, 1H)(m, 7 H) 2.933 (d, J=13.5 Hz, 1 H) 3.429 (ddd, J=13, 10.5, 3.5 Hz, 1 H)4.672 (d, J=10.5 Hz, 1 H) 6.965 (m, 1 H) 7.10-7.16 (m, 5 H) 7.206 (d,J=8.5 Hz, 2 H); Mass Spectrum (ESI) m/z=435 (M+1).

Example 431(2S,3S,5S,6R,7aR,10aS)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dimethylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one

Step A:(3S,5R,6S)-3-Allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one

L-Selectride™ (1M in THF, 5.24 ml, 5.24 mmol) was added to a solution at−10° C. of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-2-oxopentan-3-yl)piperidin-2-one(Example 149, step A, 2 g, 4.36 mmol) in THF (29.1 ml) being careful tomaintain the temperature below −7° C. The reaction was stirred for 40min then quenched into an aqueous solution of Oxone™ (10.73 g, 17.45mmol) in 60 mL water. It was noted that the temperature spiked up to 40°C. during the addition. The reaction was cooled to RT using a water/icebath and stirred at RT for 1 h, then diluted with ethyl acetate. Thelayers were separated and the aq layer was extracted with ethyl acetate.The combined organics were washed with brine and dried over MgSO₄,filtered and concentrated. The crude material was dried under highvacuum overnight. Purification by column chromatography using 10-20%acetone in hexanes afforded the title compound.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.21-7.27 (m, 2 H), 7.16 (ddd, J=8,2, 1.2 Hz, 1 H), 7.10 (t, J=7.7 Hz, 1 H), 6.95-7.07 (m, 2 H), 6.93 (t,J=1.8 Hz, 1 H), 6.70 (dt, J=7.5, 1.2 Hz, 1 H), 5.80-5.92 (m, 1 H),5.13-5.25 (m, 2 H), 4.66 (br s, 1 H), 4.37 (d, J=10.6 Hz, 1 H),3.52-4.11 (m, 1 H), 3.20 (ddd, J=13.4, 10.5, 3.2 Hz, 1 H), 2.61 (d,J=7.4 Hz, 3 H), 2.11-2.30 (m, 1 H), 2.06 (t, J=13.7 Hz, 1 H), 1.95 (dd,J=13.7, 3.3 Hz, 1H), 1.32-1.42 (m, 1 H), 1.22 (d, J=6.3 Hz, 3 H), 0.59(br s, 3 H). LC/MS (M+H) m/z=460.2.

Step B:(2S,3S,5S,6R,8S)-8-Allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium4-methylbenzenesulfonate

A solution of(3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-((2S,3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one(Example 431, Step A, 600 mg, 1.303 mmol) in toluene (43 mL) withpyridinium p-toluenesulfonate (PPTS, 327 mg, 1.30 mmol) was treated for1 h under Dean-Stark conditions. When monitoring by NMR indicated about95 to 97% completion, the reaction was treated with an additional 3% (10mg) PPTS and returned to reflux for 30 min. The reaction mixture wasconcentrated under high vacuum and used as is for subsequent reactions.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 8.15-7.10 (series of m, 12H), 5.89 (ddt,J=17.4, 10.3, 7.3, Hz, 1 H), 5.38 (d, J=11.0 Hz, 1 H), 5.36 (dd, J=16.9,1.7 Hz, 1 H), 5.27 (dd, J=10.1, 2.1 Hz, 1 H), 5.17 (quin, J=6.3 Hz, 1H), 4.12 (td, J=6.5, 2.6 Hz, 1 H), 3.97 (ddd, J=13.7, 11.0, 3.4 Hz, 1H), 2.81 (ABX, J_(AB)=13.7 Hz, J_(AX)=7.1 Hz, 1H), 2.72 (ABX,J_(AB)=13.7 Hz, J_(Bx)=7.8 Hz, 1H), 2.43 (t, J=13.2 Hz, 1 H), 2.29 (s, 3H), 1.99 (dd, J=13.3, 3.3 Hz, 1 H), 1.57 (d, J=6.1 Hz, 3 H), 1.32 (s, 3H), 0.95 (dqd, J=14.7, 7.3, 3.4 Hz, 1 H), 0.58 (t, J=7.2 Hz, 3H), 0.45(dquin, J=14.7, 7.2, Hz, 1 H). LC/MS m/z=442.2 (M+).

Step C:(2S,3S,5S,6R,7aR,10aS)-6-(3-Chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,7a-dimethylhexahydrofuro[2,3-b]oxazolo[3,2-a]pyridin-9(5H)-one

A solution of(2S,3S,5S,6R,8S)-8-allyl-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-ethyl-2,8-dimethyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-a]pyridin-4-ium4-methylbenzenesulfonate (Example 431, Step B, 775 mg, 1.261 mmol) indichloromethane (12 mL) at 0° C. with acetic acid (2.89 mL, 50.4 mmol)and tetra-n-butylammonium chloride (35.0 mg, 0.126 mmol) was treated byadding KMnO₄ (797 mg, 5.04 mmol) as a solution in water (12 mL),followed by a water rinse (12 mL).

After 20 min at 0° C., the reaction was quenched by addition of 15 mLsat. Na₂S₂O₃. The reaction was diluted with 150 mL of ethyl acetate andthe layers were separated. The organic phase was washed with water andbrine., dried over MgSO₄, filtered through Celite® (J.T. Baker,Phillipsberg, N.J., diatomaceous earth), and concentrated. The samplewas placed under high vacuum overnight to afford product with entrainedacetic acid (about 4 eq). An aliquot was purified using 60-80% ethylacetate in hexanes to afford the title compound.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.18-7.26 (m, 5 H), 7.07-7.16 (m, 2 H),7.05 (dt, J=7.0, 1.7 Hz, 1 H), 3.92 (quin, J=6.1 Hz, 1 H), 3.84 (d,J=10.8 Hz, 1 H), 3.48 (d, J=17.4 Hz, 1 H), 3.34-3.42 (m, 1 H), 2.52-2.56(m, 1 H), 2.34 (d, J=17.6 Hz, 1 H), 1.92 (ABX, J_(AB)=13.9 Hz,J_(AX)=13.2 Hz, 1 H), 1.82 (ABX, J_(AB)=13.9 Hz, J_(BX)=2.9 Hz, 1 H),1.43 (d, J=6.3 Hz, 3 H), 1.22 (s, 5 H), 0.41 (t, J=7.5 Hz, 3 H). LC/MS(M+H) m/z=460.2.

Compounds of the present invention display inhibition of the interactionbetween HDM2 and p53 in the following assays.

Homogenous Time-Resolved Fluorescence Assay (HTRF1 Assay)

The standard assay conditions for the in vitro HTRF assay consisted of a50 ul total reaction volume in black 384-well Costar polypropyleneplates in 1×PBS buffer pH 7.4, 1 mM DTT, 0.1% BSA, 2.5 nM GST-hMDM2 (aa1-188), 5 nM biotinylated-p53 (aa 1-83), 1.8 nM SA-XLent (Cisbio;Bedford, Mass.), 0.6 nM anti-GST cryptate monoclonal antibody (Cisbio;Bedford, Mass.) and 200 mM KF. Amino acid residues 1-188 of human MDM2were expressed as an amino-terminal glutathione-5-transferase (GST)fusion protein (GST-hMDM2) in Escherichia coli. Residues 1-83 of humanp53 were expressed as an amino-terminal AviTag™-TrxA-6×His fusionprotein (biotinylated p53) in E. coli. Each protein was purified fromcell paste by affinity chromatography.

Specifically, 10 uL of GST-hMDM2 was incubated with 10 ul of dilutedcompound (various concentrations, serially diluted) in 10% DMSO for 20minutes at room temperature. 20 uL of biotinylated-p53 was added to theGST-hMDM2+compound mixture, and then incubated at room temperature for60 min. 10 uL of detection buffer consisting of SA-XLent, anti-GSTcryptate antibody and KF was added to GST-hMDM2, biotinylated-p53 andcompound reaction and left at room temperature to reach equilibriumfor >4 hrs. The final concentration of DMSO in the reaction was 2%.Time-resolved fluorescence readings were measured on a microplatemultilabel reader. Percentage of inhibition was calculated relative tonutlin-3.

As the potencies of the HDM2 inhibitors increased, an improved HTRFassay (HTRF2 assay) was developed. All assay conditions remained thesame as described above, with the exception of the following changes inreagent concentrations: 0.2 nM GST-hMDM2 (1-188), 0.5 nMbiotinylated-p53 (1-83), 0.18 nM SA-XLent, and 100 mM KF.

Results are provided in the table below.

TABLE 1 Example HTRF1 IC₅₀ (μM) HTRF2 IC₅₀ (μM) 1 0.04 0.004 2 0.20 30.06 0.01 4 0.19 5 0.27 6 0.04 7 0.05 8 0.04 9 0.03 10 0.07 11 0.09 120.04 13 0.11 14 0.29 15 0.24 16 0.07 17 0.24 18 0.11 19 0.01 20 0.07 210.07 22 0.49 23 0.17 24 0.57 25 0.14 26 0.13 27 0.10 28 0.18 29 0.03 300.03 0.004 31 0.05 32 0.09 33 0.41 34 0.71 35 0.15 0.03 36 4.3 37 0.0638 0.19 39 0.30 40 0.17 41 0.32 42 0.41 43 1.97 44 0.45 45 0.55 46 0.2747 3.63 48 1.37 49 2.38 50 0.83 51 3.06 52 1.70 53 0.13 54 2.09 55 0.0956 1.89 57 1.60 58 0.70 59 0.87 60 0.16 61 0.31 62 0.09 63 0.43 64 0.2265 0.02 0.003 66 0.31 67 0.02 0.002 68 0.03 0.002 69 0.06 70 0.13 710.02 0.003 72 0.06 73 0.03 0.006 74 0.07 75 0.03 0.005 76 0.22 77 0.2678 0.53 79 0.58 80 0.08 81 0.49 82 0.02 83 0.03 84 1.76 85 1.98 86 0.0187 0.02 88 0.84 89 0.08 90 0.04 91 0.01 0.004 92 0.04 93 0.01 0.003 940.01 95 0.03 0.009 96 0.02 0.008 97 0.01 0.002 98 0.01 0.004 99 0.010.002 100 0.02 101 0.02 0.006 102 0.05 103 0.28 104 0.04 105 1.09 1060.19 107 0.21 108 0.11 109 0.30 110 0.34 111 0.61 112 0.23 113 0.03 1140.03 115 <0.01 0.001 116 0.39 117 0.71 118 0.65 119 0.12 120 0.56 1210.05 122 0.05 0.011 123 0.92 124 0.02 125 0.02 0.005

TABLE 2 Example HTRF1 IC₅₀ (μM) HTRF2 IC₅₀ (μM) 126 0.012 127 0.02 1280.01 0.001 129 0.01 0.001 130 0.01 0.003 131 0.07 132 0.12 0.070 1330.01 0.002 134 0.01 0.002 135 0.01 136 0.01 0.001 137 0.01 0.002 1380.01 0.002 139 <0.01 0.001 140 0.01 0.004 141 <0.01 0.001 142 0.01 0.001143 0.03 0.019 144 0.04 0.014 145 0.01 0.004 146 0.01 0.004 147 0.010.002 148 <0.01 0.001 149 0.04 0.006 150 0.01 0.002 151 0.02 0.006 1520.01 0.001 153 0.002 154 0.01 0.002 155 0.011 156 157 0.01 0.002 1580.01 159 0.01 0.002 160 0.01 161 0.10 162 0.006 163 0.053 164 0.049 1650.026 166 0.044 167 0.064 168 0.058 169 0.002 170 0.106 171 0.028 1720.001 173 0.015 174 0.002 175 0.001 176 0.003 177 0.053 178 0.02 0.006179 0.04 180 0.03 0.008 181 0.002 182 0.004 183 0.003 184 0.013 185 0.020.002 186 0.007 187 0.003 188 0.001 189 0.003 190 0.005 191 0.001 1920.001 193 0.001 194 0.005 195 0.002 196 <0.001 197 <0.001 198 <0.001 1990.001 200 0.001 201 0.044 202 0.002 203 0.001 204 0.002 205 0.01 0.001206 0.01 0.003 207 0.04 0.009 208 0.02 0.007 209 0.07 0.009 210 0.010.002 211 0.02 0.004 212 0.03 0.005 213 0.03 214 0.02 0.003 215 0.040.006 216 0.03 0.003 217 0.03 0.005 218 0.08 0.019 219 0.03 0.012 2200.03 221 0.02 0.003 222 0.01 0.001 223 0.02 0.004 224 0.001 225 0.002226 0.09 227 0.07 228 0.04 229 0.001 230 0.03 0.010 231 0.08 232 0.08233 0.08 234 0.05 0.011 235 0.06 236 0.01 237 0.04 0.009 238 0.001 239240 0.05 241 0.02 0.003 242 0.03 243 0.03 244 0.04 245 0.03 0.009 2460.02 0.003  247-A 0.100  247-B 0.371 248 0.100 249 0.03 0.006 250 0.010.001 251 0.01 0.001 252 0.06 253 0.001 254 <0.001 255 <0.001 256 <0.01<0.001 257 0.001 258 0.08 0.002 259 0.002 260 0.007 261 0.001 262 0.020.003

TABLE 3 Example HTRF1 IC₅₀ (μM) HTRF2 IC₅₀ (μM) 263 0.0002 264 0.0003265 0.0005 266 0.0005 267 0.0003 268 0.0001 269 0.0001 270 0.0055 2720.0001 273 0.0002 274 0.0002 275 0.0003 276 0.0005 277 0.0002 278 0.0002279 0.0005 280 0.0006 281 0.0003 282 0.0002 283 0.0007 284 0.0015 2850.0008 286 0.0006 287 0.0003 288 0.0135 289 0.0003 290 291 292 0.0009293 0.0008 294 0.0007 295 0.0018 296 0.0044 297 0.0161 298 0.0013 2990.0100 300 301 0.0003 302 0.0004 303 0.0005 304 0.0003 305 0.0005 3060.0003 307 0.0003 308 0.0001 309 0.0002 310 0.0002 311 0.0001 312 0.0112313 0.0002 314 0.0001 315 0.0014 316 0.0029 317 0.0012 318 0.0029 3190.0024 320 0.0005 321 0.0013 322 0.0001 323 0.0002 324 0.0003 325 0.0016326 0.0004 327 0.0004 328 0.0014 329 0.0016 330 0.0002 331 0.0002 3320.0003 333 0.0002 334 0.0001 335 0.0003 336 0.0018 337 0.0006 338 0.0003339 0.0003 340 0.0002 341 0.0002 342 0.0001 343 0.0002 344 0.0004 3450.0002 346 0.0001 347 0.0003 348 0.0003 349 0.0001 350 0.0001 351 0.0001352 0.0002 353 0.0001 354 0.0001 355 0.0006 356 0.0009 357 0.0002 3580.0001 359 0.0002 360 0.0003 361 0.0005 362 0.0010 363 0.0002 364 0.0003365 0.0008 366 0.0001 367 0.0026 368 0.0019 369 0.0006 370 0.0004 3710.0001 372 0.0002 373 0.0002 374 0.0002 375 0.0001 376 0.0010 377 0.0002378 0.0001 379 0.0001 380 0.0006 381 0.0001 382 0.0002 383 0.0005 3840.0005 385 386 0.0018 387 0.0070 388 389 0.0014 390 391 0.0050 3920.1230 393 0.0007 394 0.0004 395 0.0005 396 0.0002 397 0.0002 398 0.0001399 0.0001 400 0.0038 401 0.0015 402 0.0046 403 0.0040 404 0.0009 405406 407 408 0.0035 409 410 0.0026 411 412 413 0.0010 414 0.0238 4150.0010 416 0.0027 417 0.0013 418 0.0183 419 0.0034 420 0.1230 421 0.1940422 0.1040 423 0.0231 424 0.1300 425 0.2750 426 0.0526 427 0.1190 4280.0041 429 0.01 0.0024 430 0.02 431 0.0018

Compounds in the present invention display activation ofcyclin-dependent kinase inhibitor p21^(WAF1/CIP1)

p21 TagMan® Assay

Inhibition of the interaction between hMDM2 and p53 results inactivation of the p53 pathway via stabilization and accumulation of p53.p53 activates the transcription of many genes, one of which is_(p21)^(WAF1/CIP1). In order to assess the potency of hMDM2 inhibitors,quantitative reverse transcription polymerase chain reaction (qRT-PCR orTagMan®) was used to measure the levels of p21 transcript incompound-treated cells relative to dimethyl sulfoxide (DMSO)-treatedcontrol cells.

On Day 1, SJSA-1 cells were plated at a density of 3×10⁴ cells/well in96-well cell culture plates in 100 ul of growth medium (RPMI 1640; 10 mMHEPES; 1 mM sodium pyruvate; 1×Penicillin-Streptomycin-Glutamine (PSQ);and 10% fetal bovine serum (all reagents from Invitrogen; Carlsbad,Calif.)). The cells were cultured overnight at 37° C. and 5% CO₂.

On Day 2, hMDM2 inhibitors were serially diluted in DMSO (Sigma-Aldrich;St. Louis, Mo.). 5 ul of each compound dilution was added to 245 ul offiltered assay medium (RPMI 1640, 10 mM HEPES, 1 mM sodium pyruvate, and1×PSQ), containing 10% FBS. Alternatively, the assay was also run in thepresence of 10% human serum or 10% mouse serum, or in the absence of anyserum. The growth medium was removed from the plated SJSA-1 cells andreplaced with 100 ul/well of assay medium. Then 100 ul of mediumcontaining diluted inhibitor was added to each well, to a final volumeof 200 ul. The compound dose titration yielded final concentrationsranging from 0.049 uM-50 uM, plus a DMSO control. The cells wereincubated in the presence of inhibitor at 37° C. and 5% CO₂ for 7 hours.At the end of the incubation period, the medium was removed from thecells, and the plates were stored at −80° C.

On Day 3, total RNA was purified from the inhibitor- and DMSO-treatedSJSA-1 cells using the Qiagen BioRobot Universal workstation followingthe RNeasy 96 BioRobot 8000 kit protocol from the manufacturer (Qiagen;Valencia, Calif.), with the following exceptions: the protocol beganwith RLT lysis buffer addition, omitted DNase treatment, omittedaddition of Top Elute fluid, and changed the final elution volume to 120ul. After the BioRobot Universal finished the RNA extraction procedure,the collection plate containing total RNA from each well was brieflycentrifuged to collect the eluate at the bottom of the tubes.

To measure the levels of p21 transcript present, qRT-PCR was used. Thelevels of both p21 and the housekeeping gene, glyceraldehyde 3-phosphatedehydrogenase (GAPDH) were assayed from total RNA from each inhibitor-or DMSO-treated well in technical duplicates. Each qRT-PCR assay wellcontained the following components from the TaqMan® One-Step RT-PCRMaster Mix Reagents Kit (Invitrogen): 10 ul of 2×TagMan® Universal PCRMaster Mix, 0.5 ul of 40×Multiscribe™ Reverse Transcriptase/RNaseInhibitor Mix, 1 ul of either p21 20× TagMan® Gene Expression Assay(Invitrogen) or 1 ul of GAPDH 20×TagMan® Gene Expression Assay(Invitrogen), plus 5 ul of total RNA and 3.5 ul of DEPC—H₂O (EMDChemicals; Gibbstown, N.J.). The qRT-PCR reactions were assayed on theApplied Biosystems Prism 7900HT instrument, using the relativequantification (delta delta Ct) method with the following cyclingconditions: 30 minutes at 48° C., followed by 10 minutes at 95° C., then40 cycles of 15 seconds at 95° C. and 1 minute at 60° C. The data wereanalyzed with Applied Biosystems SDS2.2 software, using GAPDH as theendogenous control and DMSO-treated samples as the calibrator. TheSDS2.2 software calculated relative quantification (RQ) or fold increaseof p21 levels relative to DMSO control for each treated sample. Maximum(100%) p21 fold induction was defined by the maximum of a fitted curveof a reference compound. The p21 fold induction at each inhibitor dosetested was converted to a value representing percentage of maximum.Dose-response curves were generated using XLFit software (ID BusinessSolutions, Alameda, Calif.) to calculate IC₅₀ transit values for eachinhibitor tested.

What is claimed is:
 1. The compound2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-y)aceticacid.
 2. The compound2-(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid, or a pharmaceutically acceptable salt thereof.
 3. A pharmaceuticalcomposition comprising2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)aceticacid together with a pharmaceutically acceptable excipient, diluent orcarrier.
 4. A pharmaceutical composition comprising2-(3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3methyl-2-oxopiperidin-3-yl)acetic acid, or a pharmaceutically acceptablesalt thereof, together with a pharmaceutically acceptable excipient,diluent or carrier.